4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine derivatives as janus kinase inhibitors

ABSTRACT

There are provided compounds of formula (I), wherein X, Ak, s, L, Q, R 1  and R 2  have meanings given in the description, which compounds have antiinflammatory activity (e.g. through inhibition of one or more of members of the JAK family) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national stage filing, under 35 U.S.C. §371(c), of International Application No. PCT/GB2016/053387, filed onNov. 2, 2016, which claims priority to United Kingdom Patent ApplicationNo. 1606968.4, filed on Apr. 21, 2016; and United Kingdom PatentApplication No. 1519381.6, filed on Nov. 3, 2015. The entire contents ofeach of the aforementioned applications are incorporated herein byreference.

This invention relates, inter alia, to compounds which areantiinflammatory agents (e.g., through inhibition of one or more ofmembers of the Janus kinase (JAK) family). The invention also relates tothe use of such compounds in therapy, including in mono- and combinationtherapies, especially in the treatment of inflammatory diseases,including inflammatory diseases of the lung (such as asthma and chronicobstructive pulmonary disease (COPD)), eye (such as uveitis or dry eyedisease (DED, also known as keratoconjunctivitis sicca andxerophthalmia)) and gastrointestinal tract (such as Crohn's disease (CD)and ulcerative colitis (UC)).

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

The JAKs are a family of intracellular tyrosine kinases that play anessential role in the signalling of numerous cytokines implicated in thepathogenesis of inflammatory diseases and are critical to both innateand adaptive immunities (Clark, J. D.; Flanagan, M. E.; Telliez, J.-B.J. Med. Chem. 2014, 57, 5023-5038). The family comprises four members,JAK1, JAK2 and TYK2—all of which are expressed ubiquitously—and JAK3,found only in hematopoietic cells. These enzymes show high sequencehomology and are constitutively bound to the cytoplasmic tail ofcytokine receptors. When a cytokine binds to its receptor,multimerization (dimerization or higher order complexes) of receptorsubunits occurs, bringing the JAK enzymes associated with each subunitproximal to one another. JAK family members then auto- and/ortrans-phosphorylate, which triggers a series of phosphorylation eventsresulting ultimately in the phosphorylation and activation of signaltransducers and activators of transcription (STAT) proteins. Aphosphorylated STAT dimer then translocates to the nucleus of the cellwhere it binds to target genes to modulate their expression and altercellular function. Importantly, there are no known compensatory pathwaysaround JAK/STAT signalling and, as such, the JAK enzymes are essentialin regulating the cytokines that signal through these pathways. As aresult of their critical role in cytokine signalling, the JAK enzymeshave become targets for drug discovery and development endeavours thathave given rise to two marketed products, tofacitinib and ruxolitinib,as well as various compounds in development (Norman, P. Expert Opin.Investig. Drugs 2014, 23, 1067-1077). Of the two commercialisedproducts, pan-JAK inhibitor tofacitinib (Flanagan, M. E., et al. J. Med.Chem. 2010, 53, 8468-8484) is more relevant for inflammatory diseases,being marketed for the treatment of rheumatoid arthritis (Yamaoka, K.;Tanaka, Y. Expert Opin. Pharmacother. 2014, 15, 103-113) andinvestigated in the clinic for inflammatory bowel diseases (IBD), suchas UC (Sandborn, W. J., et al. New Engl. J. Med. 2012, 367, 616-624;Vuitton, L.; Koch, S.; Peyrin-Biroulet, L. Curr. Drug Targ. 2013, 14,1385-1391; Panes, J., et al. BMC Gastroenterol. 2015, 15, 14), whileJAK1/JAK2 inhibitor ruxolitinib is marketed for the treatment ofmyelofibrosis (Mesa, R. A.; Yasothan, U.; Kirkpatrick, P. Nat. Rev. DrugDiscov. 2012, 11, 103-104). Tofacitinib and other JAK inhibitors havebeen mooted as potential therapies for other immunological disorders,including COPD (Barnes, P. J. Nat. Rev. Drug Discov. 2013, 12, 543-559;Fenwick, P. S., et al. PLoS ONE 2015, 10(6), e0128757), DED (Beals, C.R.; Woldemussie, E. US Patent Application Publication US 2010/0267751,21 Oct. 2010; Liew, S. H., et al. Ophthalmology 2012, 119, 1328-1335;Huang, J.-F., et al. Ophthalmology 2012, 119, e43-e50) and uveitis(Huang, J.-F.; Zhang, Y.; Hirakawa, B., 2013 Association for Research inVision and Ophthalmology Annual Meeting, Seattle, USA, 5-9 May 2013,Abstract 2536).

JAK kinases function as homo or heterodimers dimers which are specificto cytokine receptor subunits. For example, JAK1-JAK3 heterodimersassociate with the γ-common chain of receptors to control signallingassociated with IL2, IL4, IL7, IL9, IL15 and IL21, cytokinespredominantly associated with adaptive immune functions. JAK1, however,also functions as a heterodimer with JAK2 and TYK2 to regulatesignalling through a wide array of cytokine receptors. In this manner,JAK1 modulates the signalling of several proinflammatory cytokinesassociated with the innate immune response, such as IL6 and the type Iinterferons. JAK2 is the only member of the JAK family that can operateas a homodimer. In this combination, JAK2 controls the signalling ofvarious cytokines and growth factors, such as IL3, IL5, granulocytemacrophage colony-stimulating factor, erythropoietin and thrombopoietin.

The potential importance of JAK1 to IBD is emphasised by the fact thattwo selective JAK1 inhibitors, filgotinib (GLPG0634) and ABT-494, are inphase 2 clinical trials for CD (Galien, R., et al. Gastroenterology2014, 146 (Suppl 1), S-49, Abstract 188). Filgotinib is of particularinterest for the treatment of IBD, given that, when colon biopsies fromIBD patients were treated with this compound, the regulation of IL6 andMX1 expression and a relationship with STAT3 phosphorylation wereobserved (Dupont, S., et al. Inflamm. Res. 2015, 64 (Suppl 2), S202,Abstract B252). Furthermore, filgotinib has demonstrated efficacy in themouse dextran sodium sulfate-induced model of colitis, with efficacybeing associated with the inhibition of STAT3 phosphorylation in theinflamed colon (Merciris, D., et al. 9th Congress of the EuropeanCrohn's and Colitis Organisation, Copenhagen, Denmark, 20-22 Feb. 2014,Abstract P072). JAK2 is implicated in that polymorphisms of thecorresponding gene are risk factors for both CD and UC, especially inCaucasians (Zhang, J. X., et al. Inflammation 2014, 37, 793-800). Inaddition, many components of the IL23 pathway, including JAK2 and TYK2,are true IBD susceptibility genes, suggesting a critical role for thispathway in maintaining intestinal immune homeostasis (Lees, C. W., etal. Gut 2011, 60, 1739-1753; Khor, B.; Gardet, A.; Xavier, R. J. Nature2011, 474, 307-317). It should also be noted that, when administeredorally, the JAK1/2 inhibitor AZD1480 inhibited colitis-associated coloncancer, a model of inflammation-driven tumorigenesis (Stuart, E., et al.Mol. Cancer Ther. 2014, 13, 468-474). This is important, given thatpatients with UC and CD of the colon have an increased risk ofdeveloping colorectal cancer (Farraye, F. A., et al. Gastroenterology2010, 138, 738-745). The importance of JAK3 in immune homeostasis hasbeen underscored by the observations that loss-of-function mutations inhumans result in a severe combined immunodeficiency phenotype (Casanova,J.-L.; Holland, S. M.; Notarangelo, L. D. Immunity 2012, 36, 515-528).Furthermore, the selective JAK3 inhibitor JANEX1 demonstrated activityin preclinical models of colitis (Uckun, F. M., et al. Bioorg. Med.Chem. 2008, 16, 1287-1298). Nonetheless, it has been indicated that JAK3inhibition alone is not sufficient to achieve maximal anti-inflammatoryefficacy and that additional inhibition of JAK1 is necessary to enhancecellular activity (Thoma, G.; Drückes, P.; Zerwes, H.-G. Bioorg. Med.Chem. Lett. 2014, 24, 4617-4621).

As indicated above, all of the JAK enzymes are associated with IBD inone way or another. As such, pan-JAK inhibitors may offer the bestchance of achieving efficacy in patients. In this regard, the pan-JAKinhibitor tofacitinib has demonstrated (Boland, B. S.; Sandborn, W. J.;Chang, J. T. Gastroenterol. Clin. N. Am. 2014, 43, 603-617)dose-dependent efficacy in Phase 2 clinical trials for UC, albeit athigher doses than that approved for the treatment of rheumatoidarthritis (5 mg twice-daily). Phase 3 studies are currently underway toevaluate the efficacy of this compound (10 mg twice-daily) as aninduction therapy in patients with active UC, and at 5 and 10 mgtwice-daily as a maintenance therapy in UC patients who have respondedto tofacitinib induction therapy. However, as a result of systemic JAKinhibition, tofacitinib therapy is associated with dose-limiting sideeffects, in particular, opportunistic infections, dose-related lipidabnormalities and bone marrow suppression, which is mediated throughJAK2 inhibition and results in anaemia, thrombocytopenia andneutropenia. Thus, although tofacitinib has demonstrated efficacy in UCpatients, there is a need for efficacious agents exhibiting an improvedside effect profile.

When administered by inhalation, clinical pan-JAK inhibitor PF06263276(Reference Compound; Coe, J. W., et al. WO2013/014567, 31 Jan. 2013) hasbeen reported to attenuate IL6-stimulated pSTAT induction in mouse lung.In addition, following topical administration, this compound reducedmouse ear swelling induced by an IL23 injection (Jones, P. Frontiers inMedicinal Chemistry 2015, Antwerp, Belgium, 14-16 Sep. 2015, AbstractIL23). The crystal structure of PF06263276 bound to JAK2 reveals thatthis compound interacts with the kinase employing the Type 1.5 bindingmode (Foloppe, N., et al. Bioorg. Med. Chem. 2006, 14, 1792-1804;Zuccotto, F., et al. J. Med. Chem. 2010, 53, 2681-2694; Wang, T., et al.Bioorg. Med. Chem. Lett. 2010, 20, 153-156) such that its “Northwestern”phenol terminus acts as both a hydrogen bond donor and a hydrogen bondacceptor, binding it deeply within a hydrophobic pocket. The bindingmode observed results in PF06263276 exhibiting slow-offset kinetics andan extended cellular duration of action.

We have now discovered, surprisingly, that compounds bearing certainaminoheteroaryl substituents inhibit one or more JAK enzymes andtherefore possess good anti-inflammatory properties.

Thus, according to a first aspect of the invention, there is provided acompound of formula I,

wherein:X represents halo;Ak represents C₁₋₆ alkyl optionally substituted by one or more fluorineatoms;s represents 1 or 2;L represents C(O), S(O)₂, CH₂ or a bond;Q represents a 6-membered heteroaromatic ring containing 1, 2 or 3 Natoms;R¹ represents R³;R² represents H, R³, C₁₋₆ alkyl or C₃₋₇ cycloalkyl, which latter twogroups are optionally substituted by one or more substituents selectedfrom C₁₋₄ alkyl, halo, hydroxy and oxo; or R¹ and R², together with theN-atom to which they are attached, form a 4- to 7-membered heterocyclicgroup that is fully saturated or partially unsaturated, whichheterocyclic group contains one N atom (the atom to which R¹ and R² areattached) and wherein

-   (a) the heterocyclic group contains one further heteroatom that is S    and is optionally substituted by one or more substituents selected    from halo, hydroxy, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy and C₁₋₄    hydroxyalkyl or-   (b) the heterocyclic group optionally contains one or more further    heteroatoms selected from N, O and S, is substituted by one or more    substituents selected from C₁₋₄ hydroxyalkyl, C₁₋₄ carboxyalkyl and    —(C₁₋₄ alkylene)-NR^(a)R^(b), and is optionally further substituted    by one or more substituents selected from halo, hydroxy, oxo, CO₂H,    C₁₋₄ alkyl and C₁₋₄ alkoxy or-   (c) the heterocyclic group is fused to a fully saturated or    partially unsaturated 5- or 6-membered heterocyclic ring, which    heterocylic ring contains one or more heteroatoms selected from from    N, O and S and is optionally substituted with one or more    substituents selected from oxo and C₁₋₄ alkyl;    R³ represents    -   Het^(x) or    -   C₁₋₆ alkyl substituted by        -   CO₂H,        -   —(OCH₂CH₂)₀₋₄OR^(c),        -   Het^(y),        -   Het^(z),        -   NR^(d)C(O)R^(e) or        -   S(O)₁₋₂R^(f),    -   which C₁₋₆ alkyl group is optionally further substituted by one        or more substituents selected from halo, hydroxy and oxo;        R^(a), R^(b), R^(c), R^(d) and R^(e) independently represent H        or C₁₋₄ alkyl,        or R^(a) and R^(b), together with the N-atom to which they are        attached, form a 4- to 7-membered heterocyclic group that is        fully saturated, partially unsaturated or fully aromatic and        which heterocyclic group contains one N atom (the atom to which        R^(a) and R^(b) are attached) and, optionally, one or more        further heteroatoms selected from O, S and N, and which        heterocyclic group is optionally substituted by one or more        substituents selected from halo, hydroxy, oxo, C₁₋₄ alkyl, C₁₋₄        alkoxy and C₁₋₄ hydroxyalkyl;        R^(f) represents C₁₋₆ alkyl or C₃₋₇ cycloalkyl;        Het^(x) represents, independently upon each occurrence, a 4- to        7-membered heterocyclic group that is fully saturated, partially        unsaturated or fully aromatic, which group contains one or more        heteroatoms selected from N, O and S, and which group is        optionally substituted by one or more substituents selected from        C₁₋₄ alkyl, halo, hydroxy and oxo;        Het^(y) represents, independently upon each occurrence, a 5- to        10-membered heterocyclic group that is fully aromatic, which        group contains one or more heteroatoms selected from N, O and S,        and which group is optionally substituted by one or more        substituents selected from C₁₋₄ alkyl, halo, hydroxy and oxo;        and        Het^(z) represents, independently upon each occurrence, a 4- to        7-membered heterocyclic group that is fully saturated or        partially unsaturated, which group contains one or more        heteroatoms selected from N, O and S, and which group is        substituted by oxo or hydroxy, and which group is optionally        further substituted by one or more substituents selected from        C₁₋₄ alkyl, halo, hydroxy and oxo,        or a pharmaceutically acceptable salt, solvate or isotopic        derivative thereof,        which compounds may be referred to hereinafter as “the compounds        of the invention”.

Pharmaceutically acceptable salts that may be mentioned include acidaddition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of a compound of formula I with one or more equivalents of anappropriate acid or base, optionally in a solvent, or in a medium inwhich the salt is insoluble, followed by removal of said solvent, orsaid medium, using standard techniques (e.g. in vacuo, by freeze-dryingor by filtration). Salts may also be prepared by exchanging acounter-ion of a compound of formula I in the form of a salt withanother counter-ion, for example using a suitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid additionsalts derived from mineral acids and organic acids, and salts derivedfrom metals.

For the avoidance of doubt, compounds of formula I may contain thestated atoms in any of their natural or non-natural isotopic forms. Inthis respect, embodiments of the invention that may be mentioned includethose in which:

-   (a) the compound of formula I is not isotopically enriched or    labelled with respect to any atoms of the compound; and-   (b) the compound of formula I is isotopically enriched or labelled    with respect to one or more atoms of the compound.

References herein to an “isotopic derivative” relate to the second ofthese two embodiments.

In particular embodiments of the invention, the compound of formula I isisotopically enriched or labelled (with respect to one or more atoms ofthe compound) with one or more stable isotopes. Thus, the compounds ofthe invention that may be mentioned include, for example, compounds offormula I that are isotopically enriched or labelled with one or moreatoms such as deuterium or the like.

Compounds of formula I may exhibit tautomerism. All tautomeric forms andmixtures thereof are included within the scope of the invention.

Unless otherwise specified, alkyl groups and alkoxy groups as definedherein may be straight-chain or, when there is a sufficient number (i.e.a minimum of three) of carbon atoms, be branched. Particular alkylgroups that may be mentioned include, for example, methyl, ethyl,n-propyl, iso-propyl, butyl, n-butyl and tert-butyl. Particular alkoxygroups that may be mentioned include, for example, methoxy, ethoxy,propoxy, and butoxy.

Unless otherwise specified, cycloalkyl groups as defined herein may,when there is a sufficient number (i.e. a minimum of four) of carbonatoms, be part cyclic/acyclic.

Unless otherwise specified, alkylene groups as defined herein may bestraight-chain or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be branched.

Unless otherwise stated, the point of attachment of aryl groups may bevia any atom of the ring system. However, when aryl groups are bicyclicor tricyclic, they are linked to the rest of the molecule via anaromatic ring. C₆₋₁₄ aryl groups include phenyl, naphthyl and the like.

For the avoidance of doubt, oxo substituents that may be present onheterocyclic groups represented by Het^(x), Het^(y), Het^(z), N(R¹)R²and N(R^(a))R^(b) may be attached to any appropriate atoms in theheterocyclic ring including, where valencies allow, to C-, N- and/orS-atoms within the ring (thereby forming keto, N-oxide, S(O) and/orS(O)₂ groups).

Values of Het^(x) that may be mentioned include piperidinyl (e.g.piperidin-4-yl).

Values of Het^(y) that may be mentioned include pyridinyl (e.g.pyridin-2-yl).

Values of Het^(z) that may be mentioned include isothiazolidinyl (e.g.isothiazolidin-2-yl), oxazolidinyl (e.g. oxazolidin-3-yl) or,particularly, piperidinyl (e.g. piperidin-1-yl or piperidin-4-yl),pyrrolidinyl (e.g. pyrrolidin-1-yl) and thiomorpholinyl (e.g.thiomorpholin-4-yl).

Examples of heterocyclic groups that may be formed by R¹, R² and theN-atom to which they are attached include, but are not limited to,azetidin-1-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, piperazin-1-yl,piperidin-1-yl, pyrrolidin-1-yl and thiomorpholin-4-yl.

Unless otherwise specified, the term “halo” includes references tofluoro, chloro, bromo or iodo, in particular, to fluoro, chloro orbromo, especially fluoro or chloro.

Embodiments of the invention that may be mentioned include compounds offormula I in which:

R¹ represents R³;

R² represents H, R³, C₁₋₆ alkyl or C₃₋₇ cycloalkyl, which latter twogroups are optionally substituted by one or more substituents selectedfrom C₁₋₄ alkyl, halo, hydroxy and oxo;

or R¹ and R², together with the N-atom to which they are attached, forma 4- to 7-membered heterocyclic group that is fully saturated orpartially unsaturated, which heterocyclic group contains one N atom (theatom to which R¹ and R² are attached) and wherein either

-   (a) the heterocyclic group contains one further heteroatom that is S    and is optionally substituted by one or more substituents selected    from halo, hydroxy, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy and C₁₋₄    hydroxyalkyl or-   (b) the heterocyclic group optionally contains one or more further    heteroatoms selected from N, O and S, is substituted by one or more    substituents selected from C₁₋₄ hydroxyalkyl, C₁₋₄ carboxyalkyl and    —(C₁₋₄ alkylene)-NR^(a)R^(b), and is optionally further substituted    by one or more substituents selected from halo, hydroxy, oxo, CO₂H,    C₁₋₄ alkyl and C₁₋₄ alkoxy; and    R³ represents    -   Het^(x) or    -   C₁₋₆ alkyl substituted by        -   CO₂H,        -   —(OCH₂CH₂)₀₋₄OR^(c),        -   Het^(y) or        -   Het^(z),    -   which C₁₋₆ alkyl group is optionally further substituted by one        or more substituents selected from halo, hydroxy and oxo.

Alternative embodiments of the invention that may be mentioned includethose in which one or more of the following definitions apply to thecompounds of formula I:

-   (i) R¹ and R², together with the N-atom to which they are attached,    form a 4- to 7-membered heterocyclic group that is fully saturated    or partially unsaturated, which heterocyclic group contains one N    atom (the atom to which R¹ and R² are attached),    -   and wherein the heterocyclic group is fused to a fully saturated        or partially unsaturated 5- or 6-membered heterocyclic ring,        which heterocylic ring contains one or more heteroatoms selected        from from N, O and S and is optionally substituted with one or        more substituents selected from oxo and C₁₋₄ alkyl;-   (ii) R³ represents C₁₋₆ alkyl substituted by    -   NR^(d)C(O)R^(e) or    -   S(O)₁₋₂R^(f),    -   which C₁₋₆ alkyl group is optionally further substituted by one        or more substituents selected from halo, hydroxy and oxo.

Embodiments of the invention that may be mentioned include compounds offormula I in relation to which one or more of the following apply:

-   (i) X represents chloro or, particularly, fluoro;-   (ii) Ak represents C₁₋₄ alkyl optionally substituted by one or more    fluorine atoms;-   (iii) s represents 1;-   (iv) L represents C(O);-   (v) Q represents a 6-membered heteroaromatic ring containing 2 N    atoms, such as pyrazinyl;-   (vi) R¹ represents R³;-   (vii) R² represents H, C₁₋₃ alkyl or R³;-   (viii) R¹ and R², together with the N-atom to which they are    attached, form a 4- to 6-membered heterocyclic group that is fully    saturated, which heterocyclic group contains one N atom (the atom to    which R¹ and R² are attached) and wherein    -   (a) the heterocyclic group contains one further heteroatom that        is S and is optionally substituted by one or more substituents        selected from halo, hydroxy, oxo, C₁₋₂ alkyl, C₁₋₂ alkoxy and        C₁₋₂ hydroxyalkyl, or    -   (b) the heterocyclic group optionally contains one further        heteroatom selected from N, O and S, is substituted by a        substituent selected from C₁₋₃ hydroxyalkyl, C₁₋₃ carboxyalkyl        and —(C₁₋₃ alkylene)-NR^(a)R^(b), and is optionally further        substituted by one or more hydroxy or C₁₋₂ alkyl groups, or    -   (c) the heterocyclic group is fused to a fully saturated 5- or        6-membered heterocyclic ring, which heterocylic ring contains        one or two heteroatoms selected from from N, O and S and is        optionally substituted by one to three substituents selected        from oxo and C₁₋₂ alkyl    -   (e.g. R¹ and R², together with the N-atom to which they are        attached, form a 5- or 6-membered heterocyclic group that is        fully saturated, which heterocyclic group contains one N atom        (the atom to which R¹ and R² are attached) and wherein either    -   (a) the heterocyclic group contains one further heteroatom that        is S and is optionally substituted by one or more substituents        selected from halo, hydroxy, oxo, C₁₋₂ alkyl, C₁₋₂ alkoxy and        C₁₋₂ hydroxyalkyl or    -   (b) the heterocyclic group optionally contains one further        heteroatom selected from N, O and S, is substituted by a        substituent selected from C₁₋₃ hydroxyalkyl, C₁₋₃ carboxyalkyl        and —(C₁₋₃ alkylene)-NR^(a)R^(b), and is optionally further        substituted by C₁₋₂ alkyl);-   (ix) R³ represents    -   Het^(x) or    -   C₁₋₄ alkyl substituted by (e.g. C₂-3 n-alkyl terminated by)        -   CO₂H,        -   —(OCH₂CH₂)₀₋₃OR^(c),        -   Het^(y),        -   Het^(z),        -   NR^(d)C(O)R^(e) or        -   S(O)₁₋₂R^(f),    -   (e.g. R³ represents    -   Het^(x) or    -   C₁₋₄ alkyl substituted by        -   CO₂H,        -   —(OCH₂CH₂)₀₋₁OR^(c),        -   Het^(y) or        -   Het^(z));-   (x) R^(a) and R^(b) represent H or C₁₋₂ alkyl, or R^(a) and R^(b),    together with the N-atom to which they are attached, form a 5- or    6-membered heterocyclic group that is fully saturated, partially    unsaturated or fully aromatic and which heterocyclic group contains    one N atom (the atom to which R^(a) and R^(b) are attached) and,    optionally, one or two further heteroatoms selected from O, S and N,    and which heterocyclic group is optionally substituted by one or    more substituents selected from hydroxy, oxo, C₁₋₂ alkyl, C₁₋₂    alkoxy and C₁₋₂ hydroxyalkyl;-   (xi) R^(c) represents H or C₁₋₂ alkyl;-   (xii) R^(d) and R^(e) independently represent H or, particularly,    C₁₋₂ alkyl;-   (xiii) R^(f) represents C₁₋₂ alkyl;-   (xiv) Het^(x) represents, independently upon each occurrence, a 5-    or 6-membered heterocyclic group that is fully saturated, which    group contains one or two heteroatoms selected from N, O and S, and    which group is optionally substituted by one to three substituents    selected from C₁₋₂ alkyl, halo, hydroxy and oxo;-   (xv) Het^(y) represents, independently upon each occurrence, a 5- or    6-membered heterocyclic group that is fully aromatic, which group    contains one to three heteroatoms selected from N, O and S and which    group is optionally substituted by one or more substituents selected    from C₁₋₂ alkyl, halo, hydroxy and oxo;-   (xvi) Het^(z) represents, independently upon each occurrence, a 5-    or 6-membered heterocyclic group that is fully saturated, which    group contains one or two heteroatoms selected from N, O and S, and    which group is substituted by oxo or hydroxy, and which group is    optionally further substituted by one or more substituents selected    from C₁₋₂ alkyl, halo, hydroxy and oxo.

Embodiments of the invention that may be mentioned include those inwhich the compound of formula I is a compound of formula Ia or Ib,

wherein X, Ak, L, Q, R¹ and R² are as hereinbefore defined.

Embodiments of the invention that may be mentioned include those inwhich one or more of the following definitions apply to the compounds offormula I, la or Ib:

-   (i) X represents fluoro;-   (ii) Ak represents C₁₋₃ alkyl, such as ethyl;-   (iii) L represents C(O);-   (iv) Q represents pyrazinyl;-   (v) R¹ represents R³;-   (vi) R² represents H, methyl or R³;-   (vii) R¹ and R², together with the N-atom to which they are    attached, form a 5- or 6-membered heterocyclic group that is fully    saturated, which heterocyclic group contains one N atom (the atom to    which R¹ and R² are attached) and wherein either    -   (a) the heterocyclic group contains one further heteroatom that        is S and is optionally substituted by one or more substituents        selected from hydroxy, oxo and methyl or    -   (b) the heterocyclic group optionally contains one further        heteroatom selected from N, O and S, is substituted by a        substituent selected from C₁₋₂ hydroxyalkyl (e.g. hydroxymethyl)        and —(C₁₋₃ alkylene)-NR^(a)R^(b), and is optionally further        substituted by methyl;-   (viii) R³ represents    -   Het^(x) or    -   C₁₋₄ alkyl substituted by        -   CO₂H (e.g. to form —(CH₂)₃—CO₂H),        -   —(OCH₂CH₂)₀₋₂OR^(c) (e.g. to form —(CH₂)₂—(OCH₂CH₂)₂OR^(c)            or —(CH₂)₂—OR^(c)),        -   Het^(y) (e.g. to form —(CH₂)₁₋₂-Het^(y)),        -   Het^(z) (e.g. to form —(CH₂)₁₋₃-Het^(z)) or        -   NR^(d)C(O)R^(e) (e.g. to form —(CH₂)₂—NR^(d)C(O)R^(e))    -   (e.g. R³ represents    -   Het^(x) or    -   C₁₋₄ alkyl substituted by        -   CO₂H (e.g. to form —(CH₂)₃—CO₂H),        -   —OR^(c) (e.g. to form —(CH₂)₂—OR^(c)),        -   Het^(y) (e.g. to form —(CH₂)₁₋₂-Het^(y)) or        -   Het^(z) (e.g. to form —(CH₂)₁₋₃-Het^(z)));-   (ix) R^(a) and R^(b) represent H or methyl, or R^(a) and R^(b),    together with the N-atom to which they are attached, form a 5- or    6-membered heterocyclic group that is fully aromatic and which    heterocyclic group contains one N atom (the atom to which R^(a) and    R^(b) are attached) and, optionally, one or two further heteroatoms    selected from O, S and N, and which heterocyclic group is optionally    substituted by one or more substituents selected from methyl,    methoxy and hydroxymethyl;-   (x) R^(c) represents H or methyl;-   (xi) R^(d) and R^(e) independently represent H or, particularly,    methyl;-   (xii) Het^(x) represents, independently upon each occurrence, a 5-    or 6-membered heterocyclic group that is fully saturated, which    group contains one or two heteroatoms selected from N, O and S, and    which group is optionally substituted by one or two substituents    selected from methyl, hydroxy and oxo;-   (xiii) Het^(y) represents, independently upon each occurrence, a 5-    or 6-membered heterocyclic group that is fully aromatic, which group    contains one or two heteroatoms selected from N, O and S and which    group is optionally substituted by one or two methyl substituents;-   (xiv) Het^(z) represents, independently upon each occurrence, a 5-    or 6-membered heterocyclic group that is fully saturated, which    group contains one or two heteroatoms selected from N, O and S, and    which group is substituted by oxo or hydroxy, and which group is    optionally further substituted by one or more substituents selected    from methyl, hydroxy and oxo.

Further embodiments of the invention that may be mentioned include thosein which the compound of formula I is a compound of formula Ic,

wherein X, Ak, R¹ and R² are as hereinbefore defined.

Embodiments of the invention that may be mentioned include those inwhich one or more of the following definitions apply to the compounds offormula I, Ia, Ib or Ic:

-   (i) X represents fluoro;-   (ii) Ak represents ethyl;-   (iii) R¹ represents R³;-   (iv) R² represents H, methyl or R³ (e.g. R² represents methyl or    R³);-   (v) R¹ and R², together with the N-atom to which they are attached,    form a 5- or 6-membered heterocyclic group that is fully saturated,    which heterocyclic group contains one N atom (the atom to which R¹    and R² are attached) and wherein either    -   (a) the heterocyclic group contains one further heteroatom that        is S and the heterocyclic group is optionally substituted by oxo        or    -   (b) the heterocyclic group is substituted by C₁₋₂ hydroxyalkyl        (e.g. hydroxymethyl);-   (vi) R³ represents C₁₋₃ alkyl (e.g. ethyl) substituted by    -   —(OCH₂CH₂)₀₋₂OR^(c) (e.g. to form —(CH₂)₂—(OCH₂CH₂)₂OR^(c) or        —(CH₂)₂—OR^(c)),    -   Het^(z) (e.g. to form —(CH₂)₂₋₃-Het^(z)) or    -   NCH₃C(O)CH₃ (e.g. to form —(CH₂)₂—NCH₃C(O)CH₃    -   (e.g. R³ represents C₁₋₃ alkyl (e.g. ethyl) substituted by    -   —OR^(c) (e.g. to form —(CH₂)₂—OR^(c)) or    -   Het^(z) (e.g. to form —(CH₂)₂₋₃-Het^(z)));-   (vii) R^(c) represents methyl;-   (viii) Het^(z) represents a 5- or 6-membered heterocyclic group that    is fully saturated, which group contains one or two heteroatoms    selected from N, O and S, and which group is substituted by oxo and    is optionally further substituted by a substituent selected from    methyl and oxo (e.g. Het^(z) represents pyrrolidinyl or    isothiazolidinyl, such as pyrrolidin-1-yl substituted by oxo (e.g.    in the 2-position) or isothiazolidin-2-yl disubstituted by oxo in    the 1-position)    -   (e.g. Het^(z) represents a 5- or 6-membered heterocyclic group        that is fully saturated, which group contains one or two        heteroatoms (e.g. one heteroatom) selected from N, O and S, and        which group is substituted by oxo (e.g. Het^(z) represents        pyrrolidinyl, such as pyrrolidin-1-yl, substituted by oxo (e.g.        in the 2-position))).

Other compounds of formula I, Ia, Ib and Ic that may be mentionedinclude the compounds of the examples described hereinafter. Thus,embodiments of the invention that may be mentioned include those inwhich the compound of formula I, Ia, Ib and Ic is a compound selectedfrom the list:

-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(methyl(1-methylpiperidin-4-yl)amino)pyrazin-2-yl)methanone;-   4-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)(methyl)amino)butanoic    acid;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-((2-(4-hydroxypiperidin-1-yl)ethyl)amino)pyrazin-2-yl)methanone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(methyl(pyridin-2-ylmethyl)amino)    pyrazin-2-yl)methanone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-((2-(1-oxidothiomorpholino)ethyl)amino)    pyrazin-2-yl)methanone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(1-oxidothiomorpholino)    pyrazin-2-yl)methanone;-   (5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-((2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl)amino)pyrazin-2-yl)methanone;-   (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrazin-2-yl)methanone;-   (5-(bis(2-methoxyethyl)amino)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone;-   (5-(4-(2-(1H-imidazol-1-yl)ethyl)piperazin-1-yl)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone;-   1-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)    pyrazin-2-yl)(methyl)amino)ethyl)pyrrolidin-2-one;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-(4-(2-hydroxyethyl)piperazin-1-yl)pyrazin-2-yl)methanone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)amino)    pyrazin-2-yl)methanone;-   N-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)(methyl)amino)ethyl)-N-methylacetamide;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-(3-(hydroxymethyl)azetidin-1-yl)pyrazin-2-yl)methanone;-   (5-(bis(2-hydroxyethyl)amino)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((2-(methylsulfonyl)ethyl)amino)    pyrazin-2-yl)methanone;-   1-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)amino)ethyl)pyrrolidin-2-one;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)pyrazin-2-yl)methanone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazin-2-yl)methanone;-   3-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)    pyrazin-2-yl)(methyl)amino)ethyl)oxazolidin-2-one;-   (5-((2-(1,1-dioxidoisothiazolidin-2-yl)ethyl)(methyl)amino)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone;    and-   (3aR,6aS)-5-(5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)    pyrazin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione,    or a pharmaceutically acceptable salt, solvate or isotopic    derivative thereof.

Further embodiments of the invention that may be mentioned include thosein which either

-   (i) the compound of formula I, Ia, Ib or Ic represents, or-   (ii) the compound of formula I, Ia, Ib or Ic is as hereinbefore    defined, provided that is does not represent-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(1-oxidothiomorpholino)    pyrazin-2-yl)methanone;-   1-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)    pyrazin-2-yl)(methyl)amino)ethyl)pyrrolidin-2-one;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)amino)    pyrazin-2-yl)methanone;-   N-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)    pyrazin-2-yl)(methyl)amino)ethyl)-N-methylacetamide; and/or-   (5-((2-(1,1-dioxidoisothiazolidin-2-yl)ethyl)(methyl)amino)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone;    or a pharmaceutically acceptable salt, solvate or isotopic    derivative thereof-   (e.g.    (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(1-oxidothiomorpholino)pyrazin-2-yl)methanone;    and/or-   1-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)    pyrazin-2-yl)(methyl)amino)ethyl)pyrrolidin-2-one, or a    pharmaceutically acceptable salt, solvate or isotopic derivative    thereof).

Examples of salts of compounds of formula I, Ia, Ib and Ic include allpharmaceutically acceptable salts, such as, without limitation, acidaddition salts of strong mineral acids such as HCl, H₂SO₄ and HBr salts(e.g. HCl or HBr salts) and addition salts of strong organic acids suchas methanesulfonic acid.

References herein to a compound of the invention (a compound of formulaI, Ia, Ib or Ic) are intended to include references to the compound andto all pharmaceutically acceptable salts, solvates and/or tautomers ofsaid compound, unless the context specifically indicates otherwise. Inthis respect, solvates that may be mentioned include hydrates.

The compounds of the invention (compounds of formula I, Ia, Ib and Ic)are JAK kinase inhibitors and are therefore useful in medicine, inparticular for the treatment of inflammatory diseases. Further aspectsof the invention that may be mentioned therefore include the following.

-   (a) A pharmaceutical formulation comprising a compound of formula I,    Ia, Ib or Ic, as hereinbefore defined, or pharmaceutically    acceptable salt, solvate or isotopic derivative thereof, in    admixture with a pharmaceutically acceptable adjuvant, diluent or    carrier.-   (b) A combination product comprising    -   (A) a compound of formula I, Ia, Ib or Ic, as hereinbefore        defined, or pharmaceutically acceptable salt, solvate or        isotopic derivative thereof, and    -   (B) another therapeutic agent, wherein each of components (A)        and (B) is formulated in admixture with a        pharmaceutically-acceptable adjuvant, diluent or carrier.

In this aspect of the invention, the combination product may be either asingle (combination) pharmaceutical formulation or a kit-of-parts.

Thus, this aspect of the invention encompasses a pharmaceuticalformulation including a compound of formula I, Ia, Ib or Ic, ashereinbefore defined, or pharmaceutically acceptable salt, solvate orisotopic derivative thereof, and another therapeutic agent, in admixturewith a pharmaceutically acceptable adjuvant, diluent or carrier (whichformulation is hereinafter referred to as a “combined preparation”).

It also encompasses a kit of parts comprising components:

-   -   (i) a pharmaceutical formulation including a compound of formula        I, Ia, Ib or Ic, as hereinbefore defined, or pharmaceutically        acceptable salt, solvate or isotopic derivative thereof, in        admixture with a pharmaceutically acceptable adjuvant, diluent        or carrier; and    -   (ii) a pharmaceutical formulation including another therapeutic        agent, in admixture with a pharmaceutically-acceptable adjuvant,        diluent or carrier,        which components (i) and (ii) are each provided in a form that        is suitable for administration in conjunction with the other.

Component (i) of the kit of parts is thus component (A) above inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier. Similarly, component (ii) is component (B) above in admixturewith a pharmaceutically acceptable adjuvant, diluent or carrier.

-   (c) A process for preparing the pharmaceutical formulation of    aspect (a) above, said process comprising the step of admixing the    compound of formula I, Ia, Ib or Ic, as hereinbefore defined, or    pharmaceutically acceptable salt, solvate or isotopic derivative    thereof, with a pharmaceutically acceptable adjuvant, diluent or    carrier.

Embodiments of this aspect of the invention that may be mentionedinclude those in which the pharmaceutically acceptable adjuvant, diluentor carrier is a topically acceptable adjuvant, diluent or carrier(and/or wherein the process is for preparing a topical pharmaceuticalformulation, i.e. a pharmaceutical formulation that is adapted fortopical administration).

-   (d) A compound of formula I, Ia, Ib or Ic, as hereinbefore defined,    or pharmaceutically acceptable salt, solvate or isotopic derivative    thereof, for use in medicine (or for use as a medicament or as a    pharmaceutical).-   (e) A compound of formula I, Ia, Ib or Ic, as hereinbefore defined,    or pharmaceutically acceptable salt, solvate or isotopic derivative    thereof, or a pharmaceutical formulation or combination product as    defined in connection with aspect (a) or (b) of the invention, for    use in the treatment or prevention of an inflammatory disease.-   (f) The use of    -   a compound of formula I, Ia, Ib or Ic, as hereinbefore defined,        or pharmaceutically acceptable salt, solvate or isotopic        derivative thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention,        for the preparation of a medicament for the treatment or        prevention of an inflammatory disease.-   (g) A method of treating or preventing an inflammatory disease, said    method comprising administering to a subject an effective amount of    -   a compound of formula I, Ia, Ib or Ic, as hereinbefore defined,        or pharmaceutically acceptable salt, solvate or isotopic        derivative thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention.-   (h) A method of sensitizing a subject to the anti-inflammatory    effects of a corticosteroid, said method comprising administering to    the subject an effective amount of    -   a compound of formula I, Ia, Ib or Ic, as hereinbefore defined,        or pharmaceutically acceptable salt, solvate or isotopic        derivative thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention.

Embodiments of this aspect of the invention that may be mentionedinclude those in which the subject is one who has become refractory tothe anti-inflammatory effects of a corticosteroid.

References herein to “preventing an inflammatory disease” includereferences to preventing (or reducing the likelihood of) the recurrenceof an inflammatory disease in a subject who has previously suffered fromsuch a disease (e.g. a subject who has previously received treatment forthat disease, for example treatment according to the method described in(g) above).

Thus, still further aspects of the invention that may be mentionedinclude the following.

-   (i) A compound of formula I, Ia, Ib or Ic, as hereinbefore defined,    or pharmaceutically acceptable salt, solvate or isotopic derivative    thereof, or a pharmaceutical formulation or combination product as    defined in connection with aspect (a) or (b) of the invention, for    use in reducing the likelihood of the recurrence of an inflammatory    disease in a subject who has previously received treatment for that    disease (e.g. treatment with a compound of formula I, Ia, Ib or Ic,    as hereinbefore defined, or pharmaceutically acceptable salt,    solvate or isotopic derivative thereof, or a pharmaceutical    formulation or combination product as defined in connection with    aspect (a) or (b) of the invention).-   (j) The use of    -   a compound of formula I, Ia, Ib or Ic, as hereinbefore defined,        or pharmaceutically acceptable salt, solvate or isotopic        derivative thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention,        for the preparation of a medicament for reducing the likelihood        of the recurrence of an inflammatory disease in a subject who        has previously received treatment for that disease (e.g.        treatment with a compound of formula I, Ia, Ib or Ic, as        hereinbefore defined, or pharmaceutically acceptable salt,        solvate or isotopic derivative thereof, or a pharmaceutical        formulation or combination product as defined in connection with        aspect (a) or (b) of the invention).-   (k) A method of reducing the likelihood of the recurrence of an    inflammatory disease in a subject who has previously received    treatment for that disease (e.g. treatment with a compound of    formula I, Ia, Ib or Ic, as hereinbefore defined, or    pharmaceutically acceptable salt, solvate or isotopic derivative    thereof, or a pharmaceutical formulation or combination product as    defined in connection with aspect (a) or (b) of the invention), said    method comprising administering to said subject an effective amount    of    -   a compound of formula I, Ia, Ib or Ic, as hereinbefore defined,        or pharmaceutically acceptable salt, solvate or isotopic        derivative thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention.        Formulations

In relation to aspects (a) and (b) above, diluents and carriers that maybe mentioned include those suitable for parenteral, oral, topical,mucosal and rectal administration.

The pharmaceutical formulations and combination products of aspects (a)and (b) above may be prepared e.g. for parenteral, subcutaneous,intramuscular, intravenous, intra-articular, intravitreous, periocular,retrobulbar, subconjunctival, sub-Tenon, topical ocular orperi-articular administration, particularly in the form of liquidsolutions, emulsions or suspensions; for oral administration,particularly in the form of tablets or capsules, and especiallyinvolving technologies aimed at furnishing colon-targeted drug release(Patel, M. M. Expert Opin. Drug Deliv. 2011, 8 (10), 1247-1258); fortopical e.g. pulmonary or intranasal administration, particularly in theform of powders, nasal drops or aerosols and transdermal administration;for topical ocular administration, particularly in the form ofsolutions, emulsions, suspensions, ointments, implants/inserts, gels,jellies or liposomal microparticle formulations (Ghate, D.; Edelhauser,H. F. Expert Opin. Drug Deliv. 2006, 3 (2), 275-287); for ocularadministration, particularly in the form of biodegradable andnon-biodegradable implants, liposomes and nanoparticles (Thrimawithana,T. R. et al. Drug Discov. Today 2011, 16 (5/6), 270-277); for mucosaladministration e.g. to buccal, sublingual or vaginal mucosa, and forrectal administration e.g. in the form of a suppository or enema.

The pharmaceutical formulations and combination products of aspects (a)and (b) above may conveniently be administered in unit dosage form andmay be prepared by any of the methods well-known in the pharmaceuticalart, for example as described in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., (1985). Formulations forparenteral administration may contain as excipients sterile water orsaline, alkylene glycols such as propylene glycol, polyalkylene glycolssuch as polyethylene glycol, oils of vegetable origin, hydrogenatednaphthalenes and the like. Formulations for nasal administration may besolid and may contain excipients, for example, lactose or dextran, ormay be aqueous or oily solutions for use in the form of nasal drops ormetered sprays. For buccal administration, typical excipients includesugars, calcium stearate, magnesium stearate, pregelatinised starch, andthe like.

Pharmaceutical formulations and combination products suitable for oraladministration may comprise one or more physiologically compatiblecarriers and/or excipients and may be in solid or liquid form. Tabletsand capsules may be prepared with binding agents, for example, syrup,acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrrolidone;fillers, such as lactose, sucrose, corn starch, calcium phosphate,sorbitol, or glycine; lubricants, such as magnesium stearate, talc,polyethylene glycol, or silica; and surfactants, such as sodium laurylsulfate. Liquid compositions may contain conventional additives such assuspending agents, for example sorbitol syrup, methyl cellulose, sugarsyrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifyingagents such as lecithin, or acacia; vegetable oils such as almond oil,coconut oil, cod liver oil, or peanut oil; preservatives such asbutylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).Liquid compositions may be encapsulated in, for example, gelatin toprovide a unit dosage form.

Solid oral dosage forms include tablets, two-piece hard shell capsulesand soft elastic gelatin (SEG) capsules. Such two-piece hard shellcapsules may be made from, for example, gelatin or hydroxylpropylmethylcellulose (HPMC).

A dry shell formulation typically comprises of about 40% to 60% w/wconcentration of gelatin, about a 20% to 30% concentration ofplasticizer (such as glycerin, sorbitol or propylene glycol) and about a30% to 40% concentration of water. Other materials such aspreservatives, dyes, opacifiers and flavours also may be present. Theliquid fill material comprises a solid drug that has been dissolved,solubilized or dispersed (with suspending agents such as beeswax,hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug invehicles or combinations of vehicles such as mineral oil, vegetableoils, triglycerides, glycols, polyols and surface-active agents.

A compound of the invention may be administered topically (e.g. to thelung, eye or intestines). Thus, embodiments of aspects (a) and (b) abovethat may be mentioned include pharmaceutical formulations andcombination products that are adapted for topical administration. Suchformulations include those in which the excipients (including anyadjuvant, diluent and/or carrier) are topically acceptable.

Topical administration to the lung may be achieved by use of an aerosolformulation. Aerosol formulations typically comprise the activeingredient suspended or dissolved in a suitable aerosol propellant, suchas a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFCpropellants include trichloromonofluoromethane (propellant 11),dichlorotetrafluoroethane (propellant 114), and dichlorodifluoromethane(propellant 12). Suitable HFC propellants include tetrafluoroethane(HFC-134a) and heptafluoropropane (HFC-227). The propellant typicallycomprises 40% to 99.5% e.g. 40% to 90% by weight of the total inhalationcomposition. The formulation may comprise excipients includingco-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitantrioleate and the like). Other possible excipients include polyethyleneglycol, polyvinylpyrrolidone, glycerine and the like. Aerosolformulations are packaged in canisters and a suitable dose is deliveredby means of a metering valve (e.g. as supplied by Bespak, Valois or 3Mor alternatively by Aptar, Coster or Vari).

Topical administration to the lung may also be achieved by use of anon-pressurised formulation such as an aqueous solution or suspension.This may be administered by means of a nebuliser e.g. one that can behand-held and portable or for home or hospital use (i.e. non-portable).The formulation may comprise excipients such as water, buffers, tonicityadjusting agents, pH adjusting agents, surfactants and co-solvents.Suspension liquid and aerosol formulations (whether pressurised orunpressurised) will typically contain the compound of the invention infinely divided form, for example with a D₅₀ of 0.5-10 μm e.g. around 1-5μm. Particle size distributions may be represented using D₁₀, D₅₀ andD₉₀ values. The D₅₀ median value of particle size distributions isdefined as the particle size in microns that divides the distribution inhalf. The measurement derived from laser diffraction is more accuratelydescribed as a volume distribution, and consequently the D₅₀ valueobtained using this procedure is more meaningfully referred to as a Dv₅₀value (median for a volume distribution). As used herein Dv values referto particle size distributions measured using laser diffraction.Similarly, D₁₀ and D₉₀ values, used in the context of laser diffraction,are taken to mean Dv₁₀ and Dv₉₀ values and refer to the particle sizewhereby 10% of the distribution lies below the D₁₀ value, and 90% of thedistribution lies below the D₉₀ value, respectively.

Topical administration to the lung may also be achieved by use of adry-powder formulation. A dry powder formulation will contain thecompound of the disclosure in finely divided form, typically with a massmean aerodynamic diameter (MMAD) of 1-10 μm or a D₅₀ of 0.5-10 μm e.g.around 1-5 μm. Powders of the compound of the invention in finelydivided form may be prepared by a micronization process or similar sizereduction process. Micronization may be performed using a jet mill suchas those manufactured by Hosokawa Alpine. The resultant particle sizedistribution may be measured using laser diffraction (e.g. with aMalvern Mastersizer 2000S instrument). The formulation will typicallycontain a topically acceptable diluent such as lactose, glucose ormannitol (preferably lactose), usually of large particle size e.g. anMMAD of 50 μm or more, e.g. 100 μm or more or a D₅₀ of 40-150 μm. Asused herein, the term “lactose” refers to a lactose-containingcomponent, including α-lactose monohydrate, β-lactose monohydrate,α-lactose anhydrous, β-lactose anhydrous and amorphous lactose. Lactosecomponents may be processed by micronization, sieving, milling,compression, agglomeration or spray drying. Commercially available formsof lactose in various forms are also encompassed, for example Lactohale®(inhalation grade lactose; DFE Pharma), InhaLac®70 (sieved lactose fordry powder inhaler; Meggle), Pharmatose® (DFE Pharma) and Respitose®(sieved inhalation grade lactose; DFE Pharma) products. In oneembodiment, the lactose component is selected from the group consistingof α-lactose monohydrate, α-lactose anhydrous and amorphous lactose.Preferably, the lactose is α-lactose monohydrate.

Dry powder formulations may also contain other excipients such as sodiumstearate, calcium stearate or magnesium stearate.

A dry powder formulation is typically delivered using a dry powderinhaler (DPI) device. Examples of dry powder delivery systems includeSPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER. Furtherexamples of dry powder delivery systems include ECLIPSE, NEXT,ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER/NEOHALER,MONODOSE, FLOWCAPS, TWINCAPS, X-CAPS, TURBOSPIN, ELPENHALER, MIATHALER,TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler,MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER,GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.

In one embodiment a compound of the present invention is provided in amicronized dry powder formulation, for example further comprisinglactose of a suitable grade optionally together with magnesium stearate,filled into a single dose device such as AEROLISER or filled into amulti dose device such as DISKUS.

The compounds of the present invention may also be administeredrectally, for example in the form of suppositories or enemas, whichinclude aqueous or oily solutions as well as suspensions and emulsions.Such compositions are prepared following standard procedures, well knownby those skilled in the art. For example, suppositories can be preparedby mixing the active ingredient with a conventional suppository basesuch as cocoa butter or other glycerides, e.g. Suppocire. In this case,the drug is mixed with a suitable non-irritating excipient which issolid at ordinary temperatures but liquid at the rectal temperature andwill therefore melt in the rectum to release the drug. Such materialsare cocoa butter and polyethylene glycols.

Generally, for compositions intended to be administered topically to theeye in the form of eye drops or eye ointments, the total amount of theinhibitor will be about 0.0001 to less than 4.0% (w/w).

Preferably, for topical ocular administration, the compositionsadministered according to the present invention will be formulated assolutions, suspensions, emulsions and other dosage forms. Aqueoussolutions are generally preferred, based on ease of formulation, as wellas a patient's ability to administer such compositions easily by meansof instilling one to two drops of the solutions in the affected eyes.However, the compositions may also be suspensions, viscous orsemi-viscous gels, or other types of solid or semi-solid compositions.Suspensions may be preferred for compounds that are sparingly soluble inwater.

The compositions administered according to the present invention mayalso include various other ingredients, including, but not limited to,tonicity agents, buffers, surfactants, stabilizing polymer,preservatives, co-solvents and viscosity building agents. Preferredpharmaceutical compositions of the present invention include theinhibitor with a tonicity agent and a buffer. The pharmaceuticalcompositions of the present invention may further optionally include asurfactant and/or a palliative agent and/or a stabilizing polymer.

Various tonicity agents may be employed to adjust the tonicity of thecomposition, preferably to that of natural tears for ophthalmiccompositions. For example, sodium chloride, potassium chloride,magnesium chloride, calcium chloride, simple sugars, such as dextrose,fructose, galactose, and/or simply polyols, such as the sugar alcoholsmannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, andhydrogenated starch hydrolysates may be added to the composition toapproximate physiological tonicity. Such an amount of tonicity agentwill vary, depending on the particular agent to be added. In general,however, the compositions will have a tonicity agent in an amountsufficient to cause the final composition to have an ophthalmicallyacceptable osmolality (generally about 150-450 mOsm, preferably 250-350mOsm and most preferably at approximately 290 mOsm). In general, thetonicity agents of the invention will present in the range of 2 to 5%w/w. Preferred tonicity agents of the invention include the simplesugars or the sugar alcohols, such as D-mannitol.

An appropriate buffer system (e.g. sodium phosphate, sodium acetate,sodium citrate, sodium borate or boric acid) may be added to thecompositions to prevent pH drift under storage conditions. Theparticular concentration will vary, depending on the agent employed.Preferably however, the buffer will be chosen to maintain a target pHwithin the range of pH 5 to 8.

Surfactants may optionally be employed to deliver higher concentrationsof inhibitor. The surfactants function to solubilise the inhibitor andstabilise colloid dispersion, such as micellar solution, microemulsion,emulsion and suspension. Examples of surfactants which may optionally beused include polysorbate, poloxamer, polyoxyl 40 stearate, polyoxylcastor oil, tyloxapol, triton, and sorbitan monolaurate. Preferredsurfactants to be employed in the invention have ahydrophile/lipophile/balance “HLB” in the range of 12.4 to 13.2 and areacceptable for ophthalmic use, such as TritonX114 and tyloxapol.

Additional agents that may be added to the ophthalmic compositions ofthe present invention are demulcents which function as a stabilisingpolymer. The stabilizing polymer should be an ionic/charged example withprecedence for topical ocular use, more specifically, a polymer thatcarries negative charge on its surface that can exhibit a zeta-potentialof (−)10-50 mV for physical stability and capable of making a dispersionin water (i.e. water soluble). A preferred stabilising polymer of theinvention would be polyelectrolyte, or polyelectrolytes if more thanone, from the family of cross-linked polyacrylates, such as carbomers,polycarbophil and Pemulen®, specifically Carbomer 974p (polyacrylicacid), at 0.1-0.5% w/w.

Other compounds may also be added to the ophthalmic compositions of thepresent invention to increase the viscosity of the carrier. Examples ofviscosity enhancing agents include, but are not limited to:polysaccharides, such as hyaluronic acid and its salts, chondroitinsulfate and its salts, dextrans, various polymers of the cellulosefamily, vinyl polymers and acrylic acid polymers.

Topical ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben,phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1,or other agents known to those skilled in the art. Such preservativesare typically employed at a level of from 0.001 to 1.0% w/v. Unit dosecompositions of the present invention will be sterile, but typicallyunpreserved. Such compositions, therefore, generally will not containpreservatives.

The medical practitioner, or other skilled person, will be able todetermine a suitable dosage for the compounds of the invention, andhence the amount of the compound of the invention that should beincluded in any particular pharmaceutical formulation (whether in unitdosage form or otherwise).

Embodiments of the invention that may be mentioned in connection withthe combination products described at (b) above include those in whichthe other therapeutic agent is one or more therapeutic agents that areknown by those skilled in the art to be suitable for treatinginflammatory diseases (e.g. the specific diseases mentioned below).

For example, for the treatment of respiratory disorders (such as COPD orasthma), the other therapeutic agent is one or more agents selected fromthe list comprising:

-   -   steroids (e.g. budesonide, beclomethasone dipropionate,        fluticasone propionate, mometasone furoate, fluticasone furoate;        a further example is ciclesonide);    -   beta agonists, particularly beta2 agonists (e.g. terbutaline,        salbutamol, salmeterol, formoterol; further examples are        vilanterol, olodaterol, reproterol and fenoterol); and    -   xanthines (e.g. theophylline).

For example, for the treatment of respiratory disorders (such as COPD orasthma), the other therapeutic agent is one or more agents selected fromthe list comprising:

-   -   muscarinic antagonists (e.g. tiotropium, umeclidinium,        glycopyrronium, aclidinium and daratropium, any of these for        example as the bromide salt); and    -   phosphodiesterase inhibitors.

Further, for the treatment of gastrointestinal disorders (such asCrohn's disease or ulcerative colitis), the other therapeutic agent maybe, for example, one or more agents selected from the list comprising:

-   -   5-aminosalicylic acid, or a prodrug thereof (such as        sulfasalazine, olsalazine or balsalazide);    -   corticosteroids (e.g. prednisolone, methylprednisolone, or        budesonide);    -   immunosuppressants (e.g. cyclosporin, tacrolimus, methotrexate,        azathioprine or 6-mercaptopurine);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol or golimumab); anti-IL12/IL23 antibodies (e.g.        ustekinumab) or small molecule IL12/IL23 inhibitors (e.g.        apilimod);    -   anti-αβ47 antibodies (e.g. vedolizumab);    -   toll-like receptor (TLR) blockers (e.g. BL-7040; Avecia        (Cambridge, UK)); MAdCAM-1 blockers (e.g. PF-00547659);    -   antibodies against the cell adhesion molecule α4-integrin (e.g.        natalizumab);    -   antibodies against the IL2 receptor a subunit (e.g. daclizumab        or basiliximab);    -   anti-Smad7 antibodies (e.g. mongersen (GED0301;        all-P-ambo-2′-deoxy-P-thioguanylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-2′-deoxy-5-methyl-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-2′-deoxy-Pthiocytidylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-5-methyl-P-thiocytidylyl-(3′→5′)-2′-deoxy-Pthioguanylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-Pthioadenylyl-(3′→5′)-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-deoxycytidine));    -   sphingosine 1-phosphate receptor 1 (S1P1) modulators (e.g.        ozanimod        ((S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile),        amiselimod (MT1303;        2-amino-2-{2-[4-(heptyloxy)-3-(trifluoromethyl)phenyl]ethyl}propane-1,3-diol)        or APD334        (2-[7-[4-cyclopentyl-3-(trifluoromethyl)benzyloxy]-1,2,3,4-tetrahydrocyclopenta[b]indol-3(R)-yl]acetic        acid));    -   STAT3 inhibitors (e.g. TAK-114;        (3E)-1-methyl-3-(2-oxo-1H-indol-3-ylidene)indol-2-one);    -   Narrow spectrum kinase inhibitors (e.g., TOP1288);    -   receptor-interacting protein-1 (RIP1) kinase inhibitors (e.g.        GSK2982772);    -   Syk inhibitors and prodrugs thereof (e.g. fostamatinib and        R-406);    -   Phosphodiesterase-4 inhibitors (e.g. tetomilast);    -   HMPL-004;    -   probiotics;    -   microbiome modulators (e.g. SGM1019);    -   Dersalazine;    -   semapimod/CPSI-2364; and    -   protein kinase C inhibitors (e.g. AEB-071)

For the treatment of eye disorders (such as uveitis andkeratoconjunctivitis sicca (dry eye)), the other therapeutic agent maybe, for example, one or more agents selected from the list comprising:

-   -   corticosteroids (e.g. dexamethasone, prednisolone, triamcinolone        acetonide, difluprednate or fluocinolone acetonide);    -   glucocorticoid agonists (e.g. mapracorat);    -   immunosuppressants (e.g. cyclosporin, voclosporin, azathioprine,        methotrexate, mycophenolate mofetil or tacrolimus);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol, ESBA-105 or golimumab);    -   anti-IL-17A antibodies (e.g. secukinumab);    -   mTOR inhibitors (e.g. sirolimus);    -   VGX-1027;    -   adenosine A3 receptor agonists (e.g. CF-101);    -   lifitegrast;    -   Narrow spectrum kinase inhibitors (e.g., TOP1630);    -   IL1 blockers (e.g. EBI-005; Hou et al. PNAS 2013, 110(10),        3913-3918);    -   RGN-259 (Thymosin 34);    -   SI-614;    -   OTX-101;    -   JNK inhibitors (e.g. XG-104);    -   MAP kinase signalling inhibitors (e.g. DA-6034;        {[2-(3,4-dimethoxyphenyl)-5-methoxy-4-oxochromen-7-yl]oxy}acetic        acid);    -   mucin stimulators (e.g. rebamipide;        2-[(4-chlorobenzoyl)amino]-3-(2-oxo-1H-quinolin-4-yl)propanoic        acid);    -   MIM-D3 (Tavilermide; see, for example, US 2013/0345395); and    -   protein kinase C inhibitors (e.g. AEB-071).        Medical Uses

The compounds of the invention may be used as monotherapies forinflammatory diseases, or in combination therapies for such diseases.

Thus, embodiments of aspects (e) to (g) above that may be mentionedinclude those in which the compound of formula I, Ia, Ib or Ic (orpharmaceutically acceptable salt, solvate or isotopic derivativethereof) is the sole pharmacologically active ingredient utilised in thetreatment.

However, in other embodiments of aspects (e) to (g) above, the compoundof formula I, Ia, Ib or Ic (or pharmaceutically acceptable salt, solvateor isotopic derivative thereof) is administered to a subject who is alsoadministered one or more other therapeutic agents (e.g. wherein the oneor more other therapeutic agents are as defined above in connection withcombination products).

When used herein, the term “inflammatory disease” specifically includesreferences to any one or more of the following:

-   (i) lung diseases or disorders having an inflammatory component,    such as cystic fibrosis, pulmonary hypertension, lung sarcoidosis,    idiopathic pulmonary fibrosis or, particularly, COPD (including    chronic bronchitis and emphysema), asthma or paediatric asthma;-   (ii) skin diseases or disorders having an inflammatory component,    such as atopic dermatitis, allergic dermatitis, contact dermatitis    or psoriasis;-   (iii) nasal diseases or disorders having an inflammatory component,    such as allergic rhinitis, rhinitis or sinusitis;-   (iv) eye diseases or disorders having an inflammatory component,    such as conjunctivitis, allergic conjunctivitis, glaucoma, diabetic    retinopathy, macular oedema (including diabetic macular oedema),    central retinal vein occlusion (CRVO), dry and/or wet age related    macular degeneration (AMD), post-operative cataract inflammation,    or, particularly, keratoconjunctivitis sicca (dry eye, also known as    xerophthalmia), uveitis (including posterior, anterior and pan    uveitis), corneal graft and limbal cell transplant rejection; and-   (v) gastrointestinal diseases or disorders having an inflammatory    component, such as gluten sensitive enteropathy (coeliac disease),    eosinophilic esophagitis, intestinal graft versus host disease or,    particularly, Crohn's disease or ulcerative colitis.

References herein to diseases having an inflammatory component includereferences to diseases that involve inflammation, whether or not thereare other (non-inflammatory) symptoms or consequences of the disease.

According to a further aspect of the invention there is provided aprocess for the preparation of a compound of formula I, which processcomprises:

(a) reaction of a compound of formula II,

wherein X, Ak, s, L and Q are as hereinbefore defined and LG representsa leaving group (e.g., halogen, methanesulfonyl or triflate), with acompound of formula III,

wherein R¹ and R² are as hereinbefore defined, for example underconditions known to those skilled in the art, such as through (i) atypical S_(N)Ar reaction in the presence of a suitable organic solvent(e.g., a polar aprotic solvent such as DMSO, DMF, THF, or mixturesthereof) and a base (e.g., DIPEA or TEA) or (ii) via a Buchwald-Hartwigcoupling (Lundgren, R. J.; Stradiotto, M. Aldrichim. Acta 2012, 45(3),59-65) employing a transition metal catalyst, e.g., palladium, and asuitable ligand, e.g., BrettPhos (J. Am. Chem. Soc. 2008, 130,13552-13554);(b) for compounds of formula I in which L represents C(O), reaction of acompound of formula IV,

wherein X, Ak and s are as hereinbefore defined, with a compound offormula VIII,

wherein Q, R¹ and R² are as hereinbefore defined, for example underconditions known to those skilled in the art, such as reaction with thecompound of formula VIII under standard amide bond forming conditions(e.g., involving a coupling agent, such as T3P or HATU (WO2013/014567),optionally in the presence of a base, such as DIPEA, in a polar aproticsolvent, such as DMF);(c) reaction of a compound of formula IV, as hereinbefore defined, witha compound of formula IX,

wherein LG¹ represents a leaving group (e.g., halogen or sulfonate) andL, Q, R¹ and R² are as hereinbefore defined, for example underconditions known to those skilled in the art, such as in the presence ofa base, such as DIPEA, and a suitable inert solvent (e.g., DMF),optionally at elevated temperatures of up to 50° C.;(d) for compounds of formula I in which L represents CH₂, reaction of acompound of formula IV, as hereinbefore defined, with a compound offormula X,

wherein Q, R¹ and R² are as hereinbefore defined, for example underconditions known to those skilled in the art, such as standard reductivealkylation conditions in the presence of a reducing agent (e.g., sodiumtriacetoxyborohydride: J. Am. Chem. Soc. 1996, 61, 3849-3862) and asuitable inert solvent (e.g., 1,2-dichloroethane, THF or DMF),optionally in the presence of acetic acid; or(e) deprotection of an protected derivative of a compound of formula I,under conditions known to those skilled in the art, wherein theprotected derivative bears a protecting group on an O- or N-atom of thecompound of formula I (and, for the avoidance of doubt, a protectedderivative of one compound of formula I may or may not represent anothercompound of formula I).

Examples of protected derivatives of compounds of formula I includethose where:

-   -   an O-atom is protected with a benzyl group, which benzyl group        may be removed by hydrogenation, for example in the presence of        a palladium catalyst (such as Pd/C);    -   an O-atom of an acid (e.g. a carboxylic acid) is protected with        an alkyl group (such as methyl, ethyl or tert-butyl), which        alkyl group may be removed by either basic hydrolysis (e.g. for        methyl or ethyl groups, by a hydrolysis reaction using an alkali        metal hydroxide such as sodium hydroxide) or acid hydrolysis        (e.g. for a tert-butyl group, by a hydrolysis reaction using an        acid such as trifluoroacetic acid);    -   an N-atom of an amine is protected with a carbamate group, such        as a benzyl or tert-butyl carbamate, which groups may be removed        under similar conditions to those used to remove benzyl or        tert-butyl groups from O-atoms.

The compound of formula II can be prepared according to proceduressimilar to those outlined in WO2013/014567. Thus, the compound offormula II can be produced (Scheme 1) by condensing an amine of formulaIV with (i) an acid of formula V under standard amide bond formingconditions (e.g., involving a coupling agent, such as T3P or HATU,optionally in the presence of a base, such as DIPEA, in a polar aproticsolvent, such as DMF), (ii) an electrophile of formula VI, i.e., an acidchloride, sulfonyl chloride, alkyl halide or activated aryl halide,where LG¹ represents a leaving group (e.g., halogen or sulfonate)displaced preferentially before LG, in the presence of a base, such asDIPEA, and a suitable inert solvent (e.g., DMF), optionally at elevatedtemperatures of up to 50° C., or (iii) an aldehyde of formula VII in thepresence of a reducing agent (e.g., sodium triacetoxyborohydride: J. Am.Chem. Soc. 1996, 61, 3849-3862) and a suitable inert solvent (e.g.,1,2-dichloroethane, THF or DMF), optionally in the presence of aceticacid.

Compounds of formula VIII, IX and X may be prepared by reacting acompound of formula III, as hereinbefore defined, with a compound offormula V, VI or VII, respectively, through either S_(N)Ar orBuchwald-Hartwig couplings, as outlined above.

Compounds of formula III, V, VI and VII are eithercommercially-available, or can be obtained using the procedures cited,or can be readily prepared by conventional methods by those skilled inthe art.

The aspects of the invention described herein (e.g. the above-mentionedcompounds, combinations, methods and uses) may have the advantage that,in the treatment of the conditions described herein, they may be moreconvenient for the physician and/or patient than, be more efficaciousthan, be less toxic than, have better selectivity over, have a broaderrange of activity than, be more potent than, produce fewer side effectsthan, have a better pharmacokinetic and/or pharmacodynamic profile than,have more suitable solid state morphology than, have better long termstability than, or may have other useful pharmacological properties oversimilar compounds, combinations, methods (treatments) or uses known inthe prior art for use in the treatment of those conditions or otherwise.

The compounds of the invention may additionally (or alternatively):

-   -   exhibit a long duration of action and/or persistence of action        (e.g. in comparison to the Reference Compound);    -   be more potent in biochemical JAK enzyme assays (e.g. in        comparison to the Reference Compound);    -   exhibit lower IC₅₀ values in cellular assays evaluating cytokine        release (e.g. in comparison to the Reference Compound);    -   produce lower systemic concentrations following oral dosing        (e.g. in comparison to the Reference Compound);    -   maintain a relatively high local drug concentration between        doses (e.g. a high local concentration relative to other        previously disclosed JAK inhibitors);    -   exhibit properties that are particularly suited to topical/local        administration (e.g. following topical/local administration, the        generation of high target tissue concentrations but low plasma        concentrations of the compounds of formula (I) and/or rapid        clearance of the compounds of formula (I) from plasma, for        example as a result of high renal or hepatic extraction);    -   display reduced cytotoxicities (e.g. in comparison to the        Reference Compound); and/or    -   exhibit enhanced solubilities (e.g. in comparison to the        Reference Compound) in biologically-relevant media, for example,        in fasted-state simulated colonic fluid (FaSSCoF; Vertzoni, M.,        et al. Pharm. Res. 2010, 27, 2187-2196).

EXPERIMENTAL SECTION

Abbreviations used herein are defined below. Any abbreviations notdefined are intended to convey their generally accepted meaning.

CHEMISTRY EXAMPLES

General Procedures

All starting materials and solvents were obtained either from commercialsources or prepared according to the literature citation. Unlessotherwise stated, all reactions were stirred. Organic solutions wereroutinely dried over anhydrous magnesium sulfate.

Preparative Reverse Phase High Performance Liquid Chromatography

Performed using UV detection at 210-400 nm with a Waters X-BridgePrep-C18, 5 μm, 19×50 mm column eluting with a H2O-MeCN gradientcontaining 0.1% ammonium bicarbonate over 10 min.

Analytical Methods

Reverse Phase High Performance Liquid Chromatography

Method 1:

Agilent Infinity, X-Select, Waters X-Select C18, 2.5 μm (4.6×30 mm) at40° C.; flow rate 2.5-4.5 mL min⁻¹ eluted with a H₂O-MeCN gradientcontaining 0.1% v/v formic acid over 4 min employing UV detection at 254nm. Gradient information: 0-3.00 min, ramped from 95% H₂O-5% MeCN to 5%H₂O-95% MeCN; 3.00-3.01 min, held at 5% H₂O-95% MeCN, flow rateincreased to 4.5 mL min⁻¹; 3.01-3.50 min, held at 5% H₂O-95% MeCN;3.50-3.60 min, returned to 95% H₂O-5% MeCN, flow rate reduced to 3.50 mLmin⁻¹; 3.60-3.90 min, held at 95% H₂O-5% MeCN; 3.90-4.00 min, held at95% H₂O-5% MeCN, flow rate reduced to 2.5 mL min⁻¹.

Method 2:

Waters Acquity UPLC C18, 1.7 μm (2.1×50 mm) at 40° C.; inject volume 2μL; flow rate 0.77 mL min⁻¹ eluted with a H₂O-MeCN gradient containing10 mM ammonium bicarbonate over 3 min employing UV detection at 210-400nm. Gradient information: 0-0.11 min, held at 95% H₂O-5% MeCN; 0.11-2.15min, ramped from 95% H₂O-5% MeCN to 5% H₂O-95% MeCN; 2.15-2.49 min, heldat 5% H₂O-95% MeCN; 2.49-2.56 min, returned to 95% H₂O-5% MeCN;2.56-3.00 min, held at 95% H₂O-5% MeCN.

¹H NMR Spectroscopy

¹H NMR spectra were acquired on a Bruker Avance III spectrometer at 400MHz using residual undeuterated solvent as reference and unlessspecified otherwise were run in DMSO-d₆.

Preparation of Compounds of the Invention Example 1(2-(6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(methyl(1-methylpiperidin-4-yl)amino)pyrazin-2-yl)methanone

(i) Intermediate A:(5-Chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone

To a stirred solution of5-ethyl-2-fluoro-4-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol.2HCl(Coe, J. W., et al. WO2013/014567, 31 Jan. 2013; 500 mg, 1.11 mmol),5-chloropyrazine-2-carboxylic acid (176 mg, 1.11 mmol) and DIPEA (970μL, 5.55 mmol) in DMF (10 mL) was added T₃P (50% in EtOAc) (1.90 mL,3.33 mmol) and the resulting yellow solution left to stir at rt for 2 h.The reaction mixture was diluted with water (10 mL) to form aprecipitate. The precipitate was collected by filtration and then washedwith water (10 mL) and diethyl ether (10 mL) to give a pale yellowsolid. The solid was dissolved in MeOH (15 mL) and concentrated in vacuoto afford the sub-title compound as a yellow solid (521 mg).

¹H NMR (400 MHz, DMSO-d₆) δ: 13.30-13.19 (m, 1H), 12.58 (s, 1H), 8.88(m, 1H), 8.78 (m, 1H), 8.34 and 8.25 (2×d, 1H), 7.39 and 7.37 (2×s, 1H),7.15-6.98 (m, 2H), 6.96-6.87 (m, 1H), 4.76 and 4.59 (2×s, 2H), 4.04 (t,1H), 3.73 (t, 1H), 2.89 (s, 1H), 2.84-2.71 (m, 2H), 2.49-2.43 (m, 1H),1.30-1.20 (m, 1H), 1.01 (m, 3H).

LCMS m/z 518 (M+H)⁺ (ES⁺)

(ii)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(methyl(1-methylpiperidin-4-yl)amino)pyrazin-2-yl)methanone

A solution of the product from step (i) (Intermediate A; 75.0 mg, 0.145mmol) in DMSO (2 mL) was added to N,1-dimethylpiperidin-4-amine (4.35mg, 0.290 mmol), followed by DIPEA (101 μL, 0.579 mmol). The solutionwas stirred at rt for 18 h. The reaction mixture was filtered and thenpurified by preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate),Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 10-40% MeCN inWater) to afford the title compound as a white solid (16.3 mg).

¹H NMR (400 MHz, DMSO-d₆) δ: 13.22 (s, 1H), 12.52 and 12.27 (2×s, 1H),9.86 (s, 1H), 8.43-8.38 (m, 1H), 8.37-8.21 (m, 1H), 8.16 (s, 1H), 7.37(s, 1H), 7.16-6.97 (m, 2H), 6.91 (d, 1H), 4.83-4.62 (m, 2H), 4.48-4.36(m, 1H), 4.01-3.86 (m, 2H), 3.30 (s, 2H), 2.99 (s, 3H), 2.90-2.73 (m,4H), 2.18 (s, 3H), 2.02 (t, 2H), 1.90-1.75 (m, 2H), 1.57 (d, 2H), 1.02(t, 3H).

LCMS m/z 610.5 (M+H)⁺ (ES⁺)

Example 2

The following compounds were prepared by reacting the appropriate aminewith Intermediate A employing methods analogous to those described abovefor Example 1 (e.g. at temperatures of 20-90° C.). The only exceptionwas Example 2(a), which was made by reacting Intermediate A with methyl4-(methylamino)butanoate, then the resulting methyl ester was isolatedand saponified with LiOH, before being purified by RP-HPLC, to affordthe corresponding acid.

(a)4-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)(methyl)amino)butanoicacid

¹H NMR (400 MHz, DMSO-d₆) δ: 13.22 (s, 1H), 12.51 (s, 1H), 9.95 (s, 1H),8.47-8.23 (m, 2H), 8.17 (s, 1H), 7.37 (s, 1H), 7.16-6.97 (m, 2H), 6.92(d, 1H), 4.91-4.60 (m, 2H), 3.94 (s, 3H), 3.60 (t, 2H), 3.12 (d, 3H),2.79 (s, 4H), 2.25-2.17 (m, 2H), 1.84-1.72 (m, 2H), 1.02 (t, 3H).

LCMS m/z 599.5 (M+H)⁺ (ES⁺)

(b)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-((2-(4-hydroxypiperidin-1-yl)ethyl)amino)pyrazin-2-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.22 (s, 1H), 12.52 and 12.26 (2×s, 1H),9.81 (s, 1H), 8.43-8.20 (m, 2H), 7.95 (d, 1H), 7.51 (s, 1H), 7.37 (s,1H), 7.17-6.97 (m, 2H), 6.91 (d, 1H), 4.86-4.59 (m, 2H), 4.54 (t, 1H),3.91 (s, 2H), 3.49-3.37 (m, 3H), 2.85-2.69 (m, 4H), 2.49-2.41 (m, 4H),2.06 (t, 2H), 1.76-1.63 (m, 2H), 1.45-1.31 (m, 2H), 1.02 (t, 3H).

LCMS m/z 626.5 (M+H)⁺ (ES⁺)

(c)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(methyl(pyridin-2-ylmethyl)amino)pyrazin-2-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), 12.53 and 12.28 (2×s, 1H),9.79 (s, 1H), 8.57-8.49 (m, 1H), 8.45-8.17 (m, 3H), 7.81-7.71 (m, 1H),7.38 (s, 1H), 7.33-7.23 (m, 2H), 7.16-6.99 (m, 2H), 6.92 (d, 1H), 4.96(s, 2H), 4.84-4.62 (m, 2H), 3.93 (s, 2H), 3.26 (s, 3H), 2.79 (s, 2H),2.50-2.44 (m, 2H), 1.02 (t, 3H).

LCMS m/z 604.5 (M+H)⁺ (ES⁺)

(d)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-((2-(1-oxidothiomorpholino)ethyl)amino)pyrazin-2-yl)methanone

¹H NMR (400 MHz, Methanol-d₄) δ: 8.39 (d, 1H), 8.28 (s, 1H), 7.96 (d,1H), 7.41 (s, 1H), 7.16 (s, 1H), 6.92 (dd, 2H), 4.95-4.89 (assume 2H,obscured by solvent), 4.06 (s, 2H), 3.59 (t, 2H), 3.38-3.34 (assume 4H,obscured by solvent), 3.18-2.81 (m, 10H), 2.73 (t, 2H), 2.55 (q, 2H),1.07 (t, 3H).

LCMS m/z 644.5 (M+H)⁺ (ES⁺)

(e)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(1-oxildothiomorpholino)pyrazin-2-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.21 (s, 1H), 12.52 and 12.29 (2×s, 1H),9.80 (s, 1H), 8.52-8.41 (m, 2H), 8.41-8.19 (m, 1H), 7.38 (s, 1H),7.18-6.98 (m, 2H), 6.91 (d, 1H), 4.91-4.59 (m, 2H), 4.44-4.25 (m, 2H),4.08-3.82 (m, 4H), 2.97 (ddd, 2H), 2.88-2.70 (m, 4H), 2.49-2.43 (assume2H, obscured by solvent), 1.02 (t, 3H).

LCMS m/z 601.4 (M+H)⁺ (ES⁺)

(f) (5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.21 (s, 1H), 12.51 and 12.26 (2×s, 1H),9.85 (s, 1H), 8.45-8.20 (m, 3H), 7.37 (s, 1H), 7.18-6.96 (m, 2H), 6.91(d, 1H), 4.83-4.60 (m, 2H), 4.03-3.82 (m, 2H), 3.72-3.59 (m, 4H), 2.78(s, 2H), 2.54-2.51 (assume 4H, obscured by solvent), 2.48-2.34 (m, 6H),2.15 (s, 6H), 1.01 (t, 3H).

LCMS m/z 639.6 (M+H)⁺ (ES⁺)

(g)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-((2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl)amino)pyrazin-2-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.22 (s, 1H), 12.52 and 12.27 (2×s, 1H),9.68 (s, 1H), 8.43-8.21 (m, 2H), 7.89 (d, 1H), 7.53 (s, 1H), 7.38 (s,1H), 7.17-6.97 (m, 2H), 6.92 (d, 1H), 4.85-4.59 (m, 2H), 4.18 (d, 1H),3.92 (s, 2H), 3.46-3.36 (m, 2H), 2.86-2.71 (m, 2H), 2.49-2.43 (assume2H, obscured by solvent), 2.42-2.20 (m, 4H), 2.14 (s, 3H), 1.74-1.62 (m,2H), 1.58-1.44 (m, 4H), 1.02 (t, 3H).

LCMS m/z 640.5 (M+H)⁺ (ES⁺)

(h)(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrazin-2-yl)methanone

¹H NMR (400 MHz, DMSO-de) δ: 13.22 (s, 1H), 12.52 and 12.29 (2×s, 1H),9.83 (s, 1H), 8.49-8.20 (m, 2H), 8.04 (s, 1H), 7.38 (s, 1H), 7.20-6.96(m, 2H), 6.92 (d, 1H), 4.95-4.58 (m, 3H), 4.24-4.11 (m, 1H), 4.08-3.86(m, 2H), 3.67-3.51 (m, 2H), 3.46-3.36 (assume 2H, obscured by solvent),2.80 (s, 2H), 2.49-2.41 (assume 2H, obscured by solvent), 2.13-1.86 (m,4H), 1.02 (t, 3H).

LCMS m/z 583.5 (M+H)⁺ (ES⁺)

(i)(5-(bis(2-methoxyethyl)amino)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.22 (s, 1H), 12.52 and 12.28 (2×s, 1H),9.83 (s, 1H), 8.44-8.12 (m, 3H), 7.37 (s, 1H), 7.19-6.96 (m, 2H), 6.91(d, 1H), 4.88-4.55 (m, 2H), 4.05-3.84 (m, 2H), 3.78 (t, 4H), 3.55 (t,4H), 3.26 (s, 6H), 2.79 (s, 2H), 2.49-2.43 (assume 2H, obscured bysolvent), 1.01 (t, 3H).

LCMS m/z 615.5 (M+H)⁺ (ES⁺)

(j)(5-(4-(2-(1H-imidazol-1-yl)ethyl)piperazin-1-yl)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.22 (s, 1H), 12.53 and 12.28 (2×s, 1H),9.87 (s, 1H), 8.49-8.19 (m, 3H), 7.66 (s, 1H), 7.38 (s, 1H), 7.21 (s,1H), 7.18-6.97 (m, 2H), 6.97-6.83 (m, 2H), 4.87-4.57 (m, 2H), 4.13 (t,2H), 4.05-3.82 (m, 2H), 3.73-3.61 (m, 4H), 2.79 (s, 2H), 2.69 (t, 2H),2.60-2.53 (m, 4H), 2.50-2.42 (assume 2H, obscured by solvent), 1.02 (t,3H).

LCMS m/z 662.5 (M+H)⁺ (ES⁺)

(k)1-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)(methyl)amino)ethyl)pyrrolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ: 13.22 (s, 1H), 12.52 and 12.31 (2×s, 1H),9.83 (s, 1H), 8.46-8.21 (m, 2H), 8.12 (s, 1H), 7.38 (s, 1H), 7.23-6.97(m, 2H), 6.92 (d, 1H), 4.93-4.60 (m, 2H), 4.07-3.86 (m, 2H), 3.79 (t,2H), 3.46-3.37 (m, 4H), 3.12 (s, 3H), 2.80 (s, 2H), 2.48-2.44 (assume2H, obscured by solvent), 2.05 (t, 2H), 1.88-1.73 (m, 2H), 1.02 (t, 3H).

LCMS m/z 624.6 (M+H)⁺ (ES⁺)

(l)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-(4-(2-hydroxyethyl)piperazin-1-yl)pyrazin-2-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), (2×s, 12.53 and 12.28, 1H),9.87 (s, 1H), 8.45-8.38 (m, 1H), 8.37-8.22 (m, 2H), 7.41-7.34 (m, 1H),7.15-6.98 (m, 2H), 6.91 (d, 1H), 4.81-4.61 (m, 2H), 4.47 (t, 2H),4.02-3.80 (m, 2H), 3.70-3.61 (m, 4H), 3.55 (q, 2H), 2.84-2.72 (m, 2H),1.01 (t, 3H). 7H under DMSO peak.

LCMS m/z 612 (M+H)⁺ (ES⁺)

(m)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)amino)pyrazin-2-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), (2×s, 12.53 and 12.28, 1H),9.87 (s, 1H), 8.45-8.38 (m, 1H), 8.37-8.22 (m, 2H), 7.41-7.34 (m, 1H),7.15-6.98 (m, 2H), 6.91 (d, 1H), 4.81-4.61 (m, 2H), 4.47 (t, 2H),4.02-3.80 (m, 2H), 3.70-3.61 (m, 4H), 3.55 (q, 2H), 2.84-2.72 (m, 2H),1.01 (t, 3H). 7H under DMSO peak.

LCMS m/z 645 (M+H)⁺ (ES⁺)

(n)N-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)(methy)amino)ethyl)-N-methylacetamide

¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), (2×s, 12.53 and 12.31, 1H),9.88 (s, 1H), 8.40 (dd, 1H), 8.38-8.17 (m, 1H), 8.15 (d, 1H), 7.37 (s,1H), 7.10 (d, 1H), 7.03 (d, 1H), 6.91 (d, 1H), 4.82-4.66 (m, 2H),3.99-3.86 (m, 2H), 3.76 (dt, 2H), 3.50 (q, 2H), (2×s, 3.17 and 3.11,3H), 2.97 (s, 2H), 2.84 (s, 1H), 2.84-2.70 (m, 2H), (2×s, 1.92 and 1.96,3H), 1.01 (t, 3H). 2H under DMSO peak.

LCMS m/z 612 (M+H)⁺ (ES⁺)

(o)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-(3-(hydroxymethyl)azetidin-1-yl)pyrazin-2-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), (2×s, 12.54 and 12.29, 1H),9.87 (s, 1H), 8.40-8.22 (m, 2H), 7.86 (s, 1H), 7.38 (s, 1H), 7.11 (d,1H), 7.03 (d, 1H), 6.92 (d, 1H), 4.87-4.79 (m, 1H), 4.74-4.66 (m, 2H),4.14 (t, 2H), 3.96 (s, 1H), 3.88 (t, 3H), 3.61 (t, 2H), 2.96-2.73 (m,3H), 1.02 (t, 3H). 2H under DMSO peak.

LCMS m/z 569 (M+H)⁺ (ES⁺)

(p)(5-(bis(2-hydroxyethyl)amino)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), (2×s, 12.53 and 12.28, 1H),9.89 (s, 1H), 8.42-8.27 (m, 2H), 8.20 (s, 1H), 7.37 (s, 1H), 7.10 (d,1H), 7.02 (d, 1H), 6.92 (d, 1H), 4.87-4.68 (m, 2H), 4.77-4.58 (m, 2H),4.00-3.86 (m, 2H), 3.73-3.57 (m, 7H), 2.86-2.70 (m, 2H), 1.01 (t, 3H).3H under DMSO peak.

LCMS m/z 587 (M+H)⁺ (ES⁺)

(q)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((2-(methylsulfonyl)ethyl)amino)pyrazin-2-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), (2×s, 12.53 and 12.27, 1H),9.88 (s, 1H), 8.81-8.19 (m, 2H), 7.98 (s, 1H), 7.94-7.85 (m, 1H), 7.38(s, 1H), 7.11 (d, 1H), 7.02 (d, 1H), 6.92 (d, 1H), 4.84-4.60 (m, 2H),4.00-3.83 (m, 2H), 3.76 (q, 2H), 3.41 (t, 2H), 3.05 (s, 3H), 2.85-2.61(m, 2H), 1.02 (t, 3H). 2H under DMSO peak.

LCMS m/z 605 (M+H)⁺ (ES⁺)

(r)1-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)amino)ethyl)pyrrolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ: 13.22 (s, 1H), (2×s, 12.53 and 12.27, 1H),9.87 (s, 1H), 8.38-8.25 (m, 2H), 7.89 (s, 1H), 7.75-7.52 (m, 1H), 7.37(s, 1H), 7.10 (d, 1H), 7.03 (d, 1H), 6.92 (d, 1H), 4.81-4.57 (m, 2H),3.99-3.80 (m, 2H), 3.52-3.43 (m, 2H), 3.42-3.33 (m, 4H), 23.75-2.71 (m,2H), 2.17 (t, 2H), 1.89 (p, 2H), 1.01 (t, 3H). 2H under DMSO peak.

LCMS m/z 610 (M+H)⁺ (ES⁺)

(s)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)pyrazin-2-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), (2×s, 12.53 and 12.27, 1H),9.88 (s, 1H), 8.41-8.22 (m, 3H), 7.38 (s, 1H), 7.18-7.07 (m, 1H), 7.01(d, 1H), 6.91 (d, 1H), 5.42-4.93 (m, 3H), 4.91-4.58 (m, 3H), 4.39-4.32(m, 1H), 4.27 (d, 1H), 4.03-3.87 (m, 2H), 3.83-3.64 (m, 4H), 3.56-3.51(m, 1H), 3.43 (dd, 1H), 2.87-2.72 (m, 2H), 1.02 (t, 3H). 2H under DMSOpeak.

LCMS m/z 645 (M+H)⁺ (ES⁺)

(t)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazin-2-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.24 (s, 1H), (2×s, 12.53 and 12.29, 1H),9.91 (s, 1H), 8.49-8.27 (m, 2H), 8.00 (s, 1H), 7.38 (s, 1H), 7.11 (d,1H), 7.03 (d, 1H), 6.92 (d, 1H), 4.81-4.67 (m, 2H), 4.00-3.84 (m, 2H),3.76-3.71 (m, 2H), 3.44 (dd, 2H), 3.02-2.89 (m, 2H), 2.85-2.72 (m, 2H),2.22 (s, 3H), 1.02 (t, 3H). 2H under water peak. 2H under DMSO peak.

LCMS m/z 608 (M+H)⁺ (ES⁺)

(u)3-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)(methyl)amino)ethyl)oxazolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), (2×s, 12.54 and 12.30, 1H),9.87 (s, 1H), 8.45-8.40 (m, 1H), 8.37-8.24 (m, 1H), 8.15 (s, 1H), 7.38(s, 1H), 7.07 (dd, 2H), 6.92 (d, 1H), 4.85-4.64 (m, 2H), 4.15 (t, 2H),4.02-3.89 (m, 2H), 3.82 (t, 2H), 3.63 (t, 2H), 3.42 (t, 2H), 3.14 (s,3H), 2.88-2.74 (m, 2H), 1.02 (t, 3H). 2H under DMSO peak.

LCMS m/z 626 (M+H)⁺ (ES⁺)

(v)(5-((2-(1,1-dioxidoisothiazolidin-2-yl)ethyl)(methyl)amino)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone

¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), (2×s, 12.53 and 12.30, 1H),9.88 (s, 1H), 8.45-8.39 (m, 1H), 8.36-8.22 (m, 1H), 8.16 (s, 1H), 7.38(s, 1H), 7.11 (d, 1H), 7.02 (d, 1H), 6.92 (d, 1H), 4.83-4.67 (m, 2H),4.01-3.87 (m, 2H), 3.81 (t, 2H), 3.30 (t, 2H), 3.20-3.11 (m, 7H),2.85-2.73 (m, 2H), 2.18 (p, 2H), 1.02 (t, 3H). 2H under DMSO peak.

LCMS m/z 660 (M+H)⁺ (ES⁺)

(w)(3aR,6aS)-5-(5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

¹H NMR (400 MHz, DMSO-d₆) δ: 13.23 (s, 1H), (2×s, 12.53 and 12.26, 1H),11.41 (s, 1H), 9.87 (s, 1H), 8.44 (s, 1H), 8.38-8.23 (m, 1H), 8.18 (s,1H), 7.43-7.35 (m, 1H), 7.15-6.99 (m, 2H), 6.92 (d, 1H), 4.83-4.64 (m,2H), 4.07 (d, 2H), 4.00-3.83 (m, 2H), 3.69-3.55 (m, 4H), 2.83-2.61 (m,2H), 1.02 (t, 3H). 2H under DMSO peak.

LCMS m/z 622 (M+H)⁺ (ES⁺)

Biological Testing: Experimental Methods

Enzyme Binding Assays (Kinomescan)

Kinase enzyme binding activities of compounds disclosed herein may bedetermined using a proprietary assay which measures active site-directedcompetition binding to an immobilized ligand (Fabian, M. A., et al.,Nature Biotechnol. 2005, 23, 329-336). These assays may be conducted byDiscoveRx (formerly Ambit; San Diego, Calif.). The percentage inhibitionproduced by incubation with a test compound may be calculated relativeto the non-inhibited control.

Cellular Assays

The compounds of the invention were studied using one or more of thefollowing assays.

(a) IFNγ Release from CD3/IL2 Stimulated PBMC Cells

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). Cells are addedto a 96 well plate, and compound at the desired concentration added 2hours prior to stimulation with a mixture of monoclonal antibody to CD3(1 μg/ml, eBioscience) and human recombinant IL2 (10 ng/ml, Peprotech).After 48 hours incubation under normal tissue culture conditions,supernatants are collected and IFNγ release determined by Sandwich ELISA(Duo-set, R&D System). The IC₅₀ is determined from the dose responsecurve.

(b) IL-2 and IFNγ Release in CD3/CD28 Stimulated LPMC Cells from IBDPatients

Lamina propria mononuclear cells (LPMCs) are isolated and purified frominflamed IBD mucosa of surgical specimens or from normal mucosa ofsurgical specimens as follows: The mucosa is removed from the deeperlayers of the surgical specimens with a scalpel and cut in fragments ofsize 3-4 mm. The epithelium is removed by washing the tissue fragmentsthree times with 1 mM EDTA (Sigma-Aldrich, Poole, UK) in HBSS(Sigma-Aldrich) with agitation using a magnetic stirrer, discarding thesupernatant after each wash. The sample is subsequently treated withtype 1A collagenase (1 mg/mL; Sigma-Aldrich) for 1 h with stirring at37° C. The resulting cell suspension is then filtered using a 100 μmcell strainer, washed twice, resuspended in RPMI-1640 medium(Sigma-Aldrich) containing 10% fetal calf serum, 100 U/mL penicillin and100 μg/mL streptomycin, and used for cell culture.

Freshly isolated LPMCs (2×10⁵ cells/well) are stimulated with 1 μg/mLα-CD3/α-CD28 for 48 h in the presence of either DMSO control orappropriate concentrations of compound. After 48 h, the supernatant isremoved and assayed for the presence of TNFα and IFNγ by R&D ELISA.Percentage inhibition of cytokine release by the test compounds iscalculated relative to the cytokine release determined for the DMSOcontrol (100%).

(c) Cell Cytotoxicity Assay

1×10⁵ Jurkat cells (immortalised human T lymphocytes) are added to theappropriate number of wells of a 96 well plate in 100 μL of media (RPMIsupplemented with 10% foetal bovine serum). 1 μL of DMSO control (finalconcentration 1.0% v/v) or test compound (final concentration 20, 5 or 1μg/mL) is added to the wells and incubated at 37° C., 5% CO₂. After 24hours, the plate is centrifuged at 1200 rpm for 3 minutes and thesupernatant discarded. Cells are then resuspended in 150 μL (finalconcentration 7.5 μg/mL) of propidium iodide (PI) in PBS and incubatedat 37° C., 5% CO₂ for 15 minutes. After 15 minutes, cells are analysedby flow cytometry (BD accuri) using the FL3 window. The % viability iscalculated as the % of cells that are PI negative in the test wellsnormalised to the DMSO control.

In Vivo Screening: Pharmacodynamics and Anti-Inflammatory Activity

(i) DSS-Induced Colitis in Mice

Non-fasted, 10-12 week old, male BDF1 mice are dosed by oral gavagetwice daily with either vehicle, reference item (5-ASA) or test compoundone day before (Day −1) stimulation of the inflammatory response bytreatment with dextran sodium sulphate (DSS). On Day 0 of the study, DSS(5% w/v) is administered in the drinking water followed by BID dosing ofthe vehicle (5 mL/kg), reference (100 mg/kg) or test compound (5 mg/kg)for 7 days. The drinking water with DSS is replenished every 3 days.During the study, animals are weighed every day and stool observationsare made and recorded as a score, based on stool consistency. At thetime of sacrifice on Day +6, the large intestine is removed and thelength and weight are recorded. Sections of the colon are taken foreither MPO analysis, to determine neutrophil infiltration, or forhistopathology scoring to determine disease severity.

(ii) TNBS-Induced Colitis in Mice

Non-fasted, 10-12 week old, male BDF1 mice are dosed by oral gavagetwice daily with either vehicle (5 mL/kg), reference item (Budesonide2.5 mg/kg) or test compound (1 or 5 mg/kg) one day before (Day −1)stimulation of the inflammatory response by treatment with2,4,6-trinitrobenzenesulphonic acid (TNBS) (15 mg/mL in 50% ethanol/50%saline). On Day 0 of the study TNBS (200 μL) is administeredintra-colonically via a plastic catheter with BID dosing of the vehicle,reference or test compound continuing for 2 or 4 days. During the study,animals are weighed every day and stool observations are made andrecorded as a score, based on stool consistency. At the time ofsacrifice on Day 2 (or Day 4), the large intestine is removed and thelength and weight recorded. Sections of the colon are taken forhistopathology scoring to determine disease severity.

(iii) Adoptive Transfer in Mice

On Study day 0, female Balb/C mice are terminated and spleens obtainedfor CD45RB^(high) cell isolation (Using SCID IBD cell Separationprotocol). Approximately 4×10⁵ cells/mL CD45RB^(high) cells are theninjected intraperitoneally (100 μL/mouse) into female SCID animals. Onstudy day 14, mice are weighed and randomized into treatment groupsbased on body weight. On Day 14, compounds are administered BID, viaoral gavage, in a dose volume of 5 mL/kg. Treatment continues untilstudy day 49, at which point the animals are necropsied 4 hours afterthe morning administration. The colon length and weight are recorded andused as a secondary endpoint in the study as a measurement of colonoedema. The colon is then divided into six cross-sections, four of whichare used for histopathology scoring (primary endpoint) and two arehomogenised for cytokine analysis. Data is given as the % inhibition ofthe induction window between naïve animals and vehicle animals, wherehigher inhibition implies closer to the non-diseased, naïve, phenotype.

(iv) Endotoxin-Induced Uveitis in Rats

Male, Lewis rats (6-8 weeks old, Charles River UK Limited) are housed incages of 3 at 19-21° C. with a 12 h light/dark cycle (07:00/19:00) andfed a standard diet of rodent chow and water ad libitum. Non-fasted ratsare weighed, individually identified on the tail with a permanentmarker, and receive a single intravitreal administration into the rightvitreous humor (5 μL dose volume) of 100 ng/animal of LPS (Escherichiacoli 0111:B4 prepared in PBS, Sigma Aldrich, UK) using a 32-gaugeneedle. Untreated rats are injected with PBS. Test compound or vehicle(4% polyoxyl 40 stearate, 4% mannitol in PBS (pH 7.4)) are administeredby the topical route onto the right eye (10 μL) of animals 1 hour priorto LPS, at the time of LPS administration, and 1, 2 and 4 hours post LPSadministration. Before administration, the solution to be administeredis sonicated to ensure a clear solution. 6 hours after LPS dosing,animals are euthanized by overdose with pentobarbitone (via cardiacpuncture). Immediately after euthanasia, 10 μL of aqueous humor iscollected from the right eye of the rats by puncture of the anteriorchamber using a 32 gauge needle under a surgical microscope. The aqueoushumor is diluted in 20 μL of PBS and total cell counts are measuredimmediately using a Countess automated cell counter (Invitrogen).Following collection of the aqueous humour, the right eye of each animalis enucleated and dissected into front (anterior) and back (posterior)sections around the lens. Each section is weighed and homogenised in 500μL of sterile PBS followed by 20 minutes centrifugation at 12000 rpm at4° C. The resulting supernatant is divided into 3 aliquots and stored at−80° C. until subsequent cytokine analysis by R&D DuoSet ELISA.

Summary of In Vitro and In Vivo Screening Results

The compound of Example 2(k) is substantially more potent than theReference Compound, displaying lower dissociation constants in thebiochemical JAK family enzyme binding assays carried out at DiscoveRx(Table 1).

TABLE 1 Dissociation constants for selected kinases determined byLeadHunter Discover Services (DiscoveRx Corporation, Fremont, CA), usingthe KINOMEscan ™ technology. Dissociation Constant (nM) Test compoundJAK1 JAK2 JAK3 TYK2 Reference Compound 2.7 0.78 1.9 1.9 Example 2(k) 1.00.047 0.092 0.13

Similarly, compounds of the examples of the present invention may besubstantially more potent than the Reference Compound on inhibiting IFNγrelease from CD3/IL2-stimulated PBMC cells (assay (a) above) and/or maydisplay enhanced viabilities in cell cytotoxicity assay (c) above (Table2).

TABLE 2 Effects of the compounds of the invention on inhibition of IFNγrelease from stimulated PBMC cells (assay (a) above) and cell viabilityin Jurkat cells (assay (c) above). Test compound PBMC IFNγ IC₅₀ (nM) %viability at 1 μg/mL Reference Compound 81.3 49 Example 1 22.6 14Example 2(a) 731.5 — Example 2(b) 87.0 — Example 2(c) 37.0 — Example2(d) 269.9 — Example 2(e) 57.6 96 Example 2(f) 49.3 16 Example 2(g)270.8 — Example 2(h) 12.1 56 Example 2(i) 14.5 53 Example 2(j) 5.3 12Example 2(k) 9.9 93 Example 2(l) 9.4 10 Example 2(m) 15.2 88 Example2(n) 29.2 87 Example 2(o) 22.5 62 Example 2(p) 153.7 — Example 2(q)113.2 94 Example 2(r) 90.8 — Example 2(s) 693.6 — Example 2(t) 15.2 18Example 2(u) 73.8 — Example 2(v) 7.5 82 Example 2(w) 941.5 —Summary of Additional StudiesDetermination of Solubilities in Fasted-State Simulated Colonic Fluid(FaSSCoF)

The solubilities of compounds of the invention in FaSSCoF at pH 6.5 aredetermined using a modification of a previously-reported procedure(Vertzoni, M., et al. Pharm. Res. 2010, 27, 2187-2196). In place of thebile salt extract employed in the original procedure (which extract isno longer available), the modified procedure uses a mixture of sodiumtaurochlorate (0.15 g), glycocholic acid (0.15 g), ursodeoxycholic acid(0.05 g), cholic acid (0.05 g), and glycodeoxycholic acid (0.05 g).These five bile acids are ground together with a mortar and pestle toproduce a fine white powder that is incorporated into the FaSSCoF, asoutlined below.

FaSSCoF Medium:

Tris(hydroxymethyl)aminomethane (Tris; 0.275 g) and maleic acid (0.44 g)are dissolved in water (35 mL) to give a solution whose pH is adjustedto 6.5 by treatment with 0.5M NaOH (ca. 12 mL). The solution is thenmade up to 50 mL with water. A portion of this Tris/maleate buffersolution (ca. 25 mL) is added to a 0.5 L round-bottomed flask, beforebeing treated with 0.00565 g of the bile acid mixture described above.Solutions of phosphatidylcholine (0.0111 g) in DCM (0.15 mL) andpalmitic acid (0.0013 g) in DCM (0.15 mL) are added, then the organicsolvent is evaporated off under reduced pressure at 40° C. until a clearsolution, with no perceptible DCM odour, is achieved. The volume of theevaporated solution is adjusted to 50 mL by addition of the remainder ofTris/maleate buffer, then BSA (0.115 g) is added, before being dissolvedby gentle agitation.

Solubility Determination:

Test compounds are suspended in the pH 6.5 FaSSCoF medium to give amaximum final concentration of 2-10 mg/mL. The suspensions areequilibrated at 25° C. for 24 h, before being filtered through a glassfibre C filter. The filtrates are then diluted as appropriate forinjection and quantification by HPLC with reference to a standard.Different volumes of the standard, diluted and undiluted samplesolutions are injected and the solubilities are calculated using thepeak areas determined by integration of the peak found at the sameretention time as the principal peak in the standard injection.

FaSSCoF solubilities are shown in Table 3 below, which reveals that,unlike the Reference Compound, compounds of the Examples exhibitedsolubilities in the FaSSCoF medium at pH 6.5 of 0.01 mg/mL or greater.

TABLE 3 Solubilities measured for certain compounds of the Examples ofthe present invention in FaSSCoF at pH 6.5. pH 6.5 FaSSCoF Solubility(mg/mL) Test compound Run 1 Run 2 Reference Compound 0.006 0.006 Example1 0.010 0.010 Example 2(h) 0.030 0.040 Example 2(k) 0.010 —Determination of Pharmacokinetic Parameters

Studies were conducted by Sai Life Sciences (Hinjewadi, Pune, India) toinvestigate the systemic pharmacokinetics and total colon tissuedistribution of compounds of the invention following a single oraladministration in male C57BL/6 mice.

A group of twenty four male mice were administered with a solution oftest compound formulated at a dose of 10 mg/10 mL/kg in aqueoushydroxypropyl-β-cyclodextrin (20% w/v in water). Blood samples(approximately 60 μL) were collected from retro-orbital plexus of eachmouse under light isoflurane anaesthesia such that the samples wereobtained at 0.5, 1, 2, 4, 6, 8, 12 and 24 hr. The blood samples werecollected from a set of three mice at each time point in a labeled microcentrifuge tube containing K₂EDTA as anticoagulant. Plasma samples wereseparated by centrifugation at 4000 rpm for 10 min and stored below −70°C. until bioanalysis. After collection of blood sample, animals werehumanely euthanized by carbon dioxide asphyxiation to collect totalcolon tissues. The colons were flushed with cold PBS (pH7.4) to removecontents. The total colon tissues were homogenized with cold PBS (pH7.4)of twice the weight of colon tissue and stored below −70° C. Totalvolume was three times the total colon tissue weights. All samples wereprocessed for analysis by protein precipitation using acetonitrile andanalyzed with a fit-for-purpose LC-MS/MS method. Pharmacokineticparameters were calculated using the non-compartmental analysis tool ofPhoenix WinNonlin® (Version 6.3).

The data catalogued in Table 4 reveal that, following oraladministration, the compound of Example 2(k) achieved substantialcolonic concentrations, while, in contrast, systemic plasma exposure wasvery low. Moreover, Example 2(k) demonstrates much highercolon-to-plasma ratios compared to the Reference Compound, as revealedin Table 5. In both of Tables 4 and 5, “P” refers to plasma and “C”refers to total colon.

TABLE 4 Mean plasma concentrations (ng/mL) or total colon levels (ng/g)obtained following oral administration of the Reference Compound andExample 2(k) to mice at 10 mg/kg in solution in 20% aqueoushydroxypropyl-β-cyclodextrin (dose volume = 10 mL/kg). Time (h) CompoundMatrix 0.5 1 2 4 6 8 12 24 Reference P 5.2 12.8 2.2 14.4 114 95.0 0.00.0 Compound C 344 102 2,366 2,972 201 2,555 3,229 16.6 Example 2(k) P2.4 2.6 1.9 1.1 3.4 4.8 1.2 0.0 C 431 1,155 5,447 7,232 4,815 15,2172,224 44.8

TABLE 5 Total colon to plasma ratios obtained following oraladministration of solutions of the Reference Compound and Example 2(k)at 10 mg/kg to mice. C_(max) AUC_(0-24 h) (ng/g or ng/mL) C_(max) (h ·ng/g or h · ng/mL) AUC_(0-24 h) Compound C P ratio C P ratio Reference3,229 114 28.2 43,739 368 119 Compound Example 2(k) 15,217 4.8 3,17097,062 20 4,853

Abbreviations

-   -   aq aqueous    -   5-ASA 5-aminosalicylic acid    -   ATP adenosine-5′-triphosphate    -   BID bis in die (twice-daily)    -   Boc tert-butoxycarbonyl    -   br broad    -   BSA bovine serum albumin    -   CD Crohn's disease    -   COPD chronic obstructive pulmonary disease    -   d doublet    -   δ chemical shift    -   DCM dichloromethane    -   DIPEA diisopropylethylamine    -   DMEM Dulbecco's modified eagle medium    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   EDTA ethylenediaminetetraacetic acid    -   ELISA enzyme-linked immunosorbent assay    -   (ES⁻) electrospray ionization, negative mode    -   (ES⁺) electrospray ionization, positive mode    -   Et ethyl    -   Et₃N triethylamine    -   EtOAc ethyl acetate    -   EtOH ethanol    -   FaSSCoF fasted-state simulated colonic fluid    -   FBS foetal bovine serum    -   FCS foetal calf serum    -   HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium        hexafluoro-phosphate    -   HBSS Hank's balanced salt solution    -   HPLC high performance liquid chromatography    -   HPMC hydroxypropylmethylcellulose    -   h, hr or hrs hour(s)    -   HRP horseradish peroxidise    -   IBD Inflammatory bowel disease    -   IFNγ interferon-γ    -   IL interleukin    -   IPA isopropyl alcohol    -   JAK Janus kinase    -   JNK c-Jun N-terminal kinase    -   LC liquid chromatography    -   LPMC lamina propria mononuclear cells    -   LPS lipopolysaccharide    -   m multiplet    -   (M+H)⁺ protonated molecular ion    -   (M−H)⁻ deprotonated molecular ion    -   Me methyl    -   MeCN acetonitrile    -   MeOH methanol    -   MHz megahertz    -   min or mins minute(s)    -   MMAD mass median aerodynamic diameter    -   MPO myeloperoxidase    -   MS mass spectrometry    -   m/z mass-to-charge ratio    -   NMP N-Methyl-2-pyrrolidone    -   NMR nuclear magnetic resonance (spectroscopy)    -   OD optical density    -   PBMC peripheral blood mononuclear cell    -   PBS phosphate buffered saline    -   Ph phenyl    -   PHA phytohaemagglutinin    -   PI propidium iodide    -   PMA phorbol myristate acetate    -   q quartet    -   rt or RT room temperature    -   RP HPLC reverse phase high performance liquid chromatography    -   rpm revolutions per minute    -   RPMI Roswell Park Memorial Institute    -   s singlet    -   sat or satd saturated    -   SCID severe combined immunodeficiency    -   SCX solid supported cation exchange (resin)    -   SDS sodium dodecyl sulfate    -   S_(N)Ar nucleophilic aromatic substitution    -   Syk Spleen tyrosine kinase    -   t triplet    -   ^(t)Bu tert-butyl    -   T3P 1-propanephosphonic acid cyclic anhydride    -   TEA triethylamine    -   THF tetrahydrofuran    -   TFA trifluoroacetic acid    -   TGFβ transforming growth factor beta    -   TNFα tumor necrosis factor alpha    -   Tris tris(hydroxymethyl)aminomethane    -   TYK2 tyrosine kinase 2    -   UC ulcerative colitis    -   UPLC ultra performance liquid chromatography    -   UV ultra-violet

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

The invention claimed is:
 1. A compound having the structure of formulaI:

or a pharmaceutically acceptable salt, solvate or isotopic derivativethereof, wherein: X is halo; Ak is C₁₋₆ alkyl optionally substitutedwith one or more fluorine atoms; s is 1 or 2; L is C(O), S(O)₂, CH₂, ora bond; Q is a 6-membered heteroaromatic ring containing 1, 2 or 3 Natoms; R¹ is R³; R² is H, methyl, or R³; or R¹ and R², together with theN-atom to which they are attached, form a 4- to 7-membered heterocyclicgroup that is fully saturated or partially unsaturated, whichheterocyclic group contains one N atom, and wherein the heterocyclicgroup (a) further contains one S atom and is optionally substituted withone or more halo, hydroxy, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy, or C₁₋₄hydroxyalkyl; or (b) optionally contains one or more further heteroatomsselected from N, O and S, is substituted with one or more C₁₋₄hydroxyalkyl, C₁₋₄ carboxyalkyl, or (C₁₋₄ alkylene)-NR^(a)R^(b), and isoptionally further substituted by one or more substituents selected fromhalo, hydroxy, oxo, CO₂H, C₁₋₄ alkyl and C₁₋₄ alkoxy; or (c) is fused toa fully saturated or partially unsaturated 5- or 6-membered heterocyclicring, which 5- or 6-membered heterocylic ring contains one or moreheteroatoms selected from N, O and S and is optionally substituted withone or more oxo or C₁₋₄ alkyl; R³ is Het^(x) or C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is substituted by one or more —CO₂H, —(OCH₂CH₂)₀₋₄OR^(c),Het^(y), Het^(z), —NR^(d)C(O)R^(e), or —S(O)₁₋₂R^(f) and is optionallyfurther substituted by one or more halo, hydroxyl, or oxo; R^(a) andR^(b) are each, independently, H or C₁₋₄ alkyl, or R^(a) and R^(b),together with the N-atom to which they are attached, form a 4- to7-membered heterocyclic group that is fully saturated, partiallyunsaturated or fully aromatic and which heterocyclic group contains oneN atom and, optionally, one or more further heteroatoms selected from O,S and N, and which heterocyclic group is optionally substituted with oneor more halo, hydroxy, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy, or C₁₋₄hydroxyalkyl; R^(c), R^(d) and R^(e) are each, independently, H or C₁₋₄alkyl, R^(f) is C₁₋₆ alkyl or C₃₋₇ cycloalkyl; Het^(x) is at eachoccurrence, independently, a 4- to 7-membered heterocyclic group that isfully saturated, partially unsaturated or fully aromatic, which groupcontains one or more heteroatoms selected from N, O and S, and whichgroup is optionally substituted by one or more C₁₋₄ alkyl, halo,hydroxyl, or oxo; Het^(y) is at each occurrence, independently, a 5- to10-membered heterocyclic group that is fully aromatic, which groupcontains one or more heteroatoms selected from N, O and S, and whichgroup is optionally substituted by one or more substituents selectedfrom C₁₋₄ alkyl, halo, hydroxy and oxo; and Het^(z) is at eachoccurrence, independently, a 4- to 7-membered heterocyclic group that isfully saturated or partially unsaturated, which group contains one ormore heteroatoms selected from N, O and S, and which group issubstituted by oxo or hydroxy, and which group is optionally furthersubstituted by one or more substituents selected from C₁₋₄ alkyl, halo,hydroxy and oxo.
 2. The compound of claim 1 having the structure offormula Ia, or a pharmaceutically acceptable salt, solvate or isotopicderivative thereof:


3. The compound of claim 1 having the structure of formula Ib, or apharmaceutically acceptable salt, solvate or isotopic derivativethereof:


4. The compound of claim 1 having the structure of formula Ic, or apharmaceutically acceptable salt, solvate or isotopic derivativethereof:


5. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein X is fluoro.
 6. Thecompound of claim 1, or a pharmaceutically acceptable salt, solvate orisotopic derivative thereof, wherein Ak is C₁₋₃ alkyl.
 7. The compoundof claim 1, or a pharmaceutically acceptable salt, solvate or isotopicderivative thereof, wherein X is fluoro and Ak is C₁₋₃ alkyl.
 8. Thecompound of claim 1, or a pharmaceutically acceptable salt, solvate orisotopic derivative thereof, wherein L is C(O).
 9. The compound of claim1, or a pharmaceutically acceptable salt, solvate or isotopic derivativethereof, wherein Q is pyrazinyl.
 10. The compound of claim 1, or apharmaceutically acceptable salt, solvate or isotopic derivativethereof, wherein L is C(O) and Q is pyrazinyl.
 11. The compound of claim1, or a pharmaceutically acceptable salt, solvate or isotopic derivativethereof, wherein: R¹ is R³; R² is H, methyl, or R³; or R¹ and R²,together with the N-atom to which they are attached, form a 5- or6-membered heterocyclic group that is fully saturated, and whereineither (a) the heterocyclic group contains one further heteroatom thatis S and the heterocyclic group is optionally substituted by one or morehydroxy, oxo, or methyl, or (b) the heterocyclic group optionallycontains one further heteroatom selected from N, O and S, is substitutedby C₁₋₂ hydroxyalkyl or -(C₁₋₃ alkylene)-NR^(a)R^(b), and is optionallyfurther substituted by methyl.
 12. The compound of claim 1, or apharmaceutically acceptable salt, solvate or isotopic derivativethereof, wherein: R³ is Het^(x) or C₁₋₄ alkyl, wherein the C₁₋₄ alkyl issubstituted by one or more —CO₂H, —(OCH₂CH₂)₀₋₂OR^(c), Het^(y), Het^(z)or NR^(d)C(O)R^(e); and/or R^(d) and R^(e) are each, independently, H ormethyl.
 13. The compound of claim 1, or a pharmaceutically acceptablesalt, solvate or isotopic derivative thereof, wherein: R^(a) and R^(b)are each, independently, H or methyl, or R^(a) and R^(b), together withthe N-atom to which they are attached, form a 5- or 6-memberedheterocyclic group that is fully aromatic, wherein the 5- or 6-memberedheterocyclic group optionally contains one or two further heteroatomsselected from O, S and N, and wherein the 5- or 6-membered heterocyclicgroup is optionally substituted by one or more methyl, methoxy, orhydroxymethyl; and/or R^(c) represents H or methyl.
 14. The compound ofclaim 1, or a pharmaceutically acceptable salt, solvate or isotopicderivative thereof, wherein: Het^(x) is at each occurrence,independently, a fully saturated 5- or 6-membered heterocyclic groupcontaining one or two heteroatoms selected from N, O, and S, whereinHet^(x) is optionally substituted by one or two methyl, hydroxyl, or oxosubstituents; Het^(y) is at each occurrence, independently, a fullyaromatic 5- or 6-membered heterocyclic group containing one or twoheteroatoms selected from N, O, and S, wherein Het^(y) is optionallysubstituted by one or two methyl substituents; and/or Het^(z) is at eachoccurrence, independently, a fully saturated 5- or 6-memberedheterocyclic group containing one or two heteroatoms selected from N, O,and S, wherein Het^(z) is substituted by oxo or hydroxyl, and whereinHet^(z) is optionally further substituted by one or more methyl,hydroxyl, or oxo substituents.
 15. The compound of claim 1, or apharmaceutically acceptable salt, solvate or isotopic derivativethereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(methyl(1-methylpiperidin-4-yl)amino)pyrazin-2-yl)methanone.16. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is4-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)(methyl)amino)butanoicacid.
 17. The compound of claim 1, or a pharmaceutically acceptablesalt, solvate or isotopic derivative thereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-((2-(4-hydroxypiperidin-1-yl)ethyl)amino)pyrazin-2-yl)methanone.18. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(methyl(pyridin-2-ylmethyl)amino)pyrazin-2-yl)methanone.19. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-((2-(1-oxidothiomorpholino)ethyl)amino)pyrazin-2-yl)methanone.20. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(1-oxidothiomorpholino)pyrazin-2-yl)methanone.21. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone.22. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-((2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl)amino)pyrazin-2-yl)methanone.23. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrazin-2-yl)methanone.24. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(5-(bis(2-methoxyethyl)amino)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone.25. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(5-(4-(2-(1H-imidazol-1-yl)ethyl)piperazin-1-yl)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone.26. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is1-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)(methyl)amino)ethyl)pyrrolidin-2-one.27. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-(4-(2-hydroxyethyl)piperazin-1-yl)pyrazin-2-yl)methanone.28. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)amino)pyrazin-2-yl)methanone.29. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound isN-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)(methyl)amino)ethyl)-N-methylacetamide.30. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-(3-(hydroxymethyl)azetidin-1-yl)pyrazin-2-yl)methanone.31. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(5-(bis(2-hydroxyethyl)amino)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone.32. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((2-(methylsulfonyl)ethyl)amino)pyrazin-2-yl)methanone.33. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is1-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)amino)ethyl)pyrrolidin-2-one.34. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)pyrazin-2-yl)methanone.35. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)(5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazin-2-yl)methanone.36. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is3-(2-((5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)(methyl)amino)ethyl)oxazolidin-2-one.37. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(5-((2-(1,1-dioxidoisothiazolidin-2-yl)ethyl)(methyl)amino)pyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone.38. The compound of claim 1, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof, wherein the compound is(3aR,6aS)-5-(5-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)pyrazin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione.
 39. A pharmaceutical formulation comprising a compound ofclaim 1, or pharmaceutically acceptable salt, solvate or isotopicderivative thereof, in admixture with a pharmaceutically acceptableadjuvant, diluent or carrier.
 40. A combination product comprising (A) acompound of claim 1, or pharmaceutically acceptable salt, solvate orisotopic derivative thereof, and (B) another therapeutic agent, whereineach of components (A) and (B) is formulated in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier.
 41. A methodof treating an inflammatory disease comprising administering to asubject an effective amount of a compound of claim 1, orpharmaceutically acceptable salt, solvate or isotopic derivativethereof, or a pharmaceutical formulation comprising a compound of claim1, or pharmaceutically acceptable salt, solvate or isotopic derivativethereof, in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier, or a combination product comprising (A) a compoundof claim 1, or pharmaceutically acceptable salt, solvate or isotopicderivative thereof, and (B) another therapeutic agent, wherein each ofcomponents (A) and (B) is formulated in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier, wherein theinflammatory disease is COPD, asthma, atopic dermatitis, allergicdermatitis, psoriasis, dry eye, xerophthalmia, uveitis, Crohn's disease,or ulcerative colitis.
 42. The method according to claim 41, wherein theinflammatory disease is uveitis, dry eye, xerophthalmia, Crohn'sdisease, ulcerative colitis, asthma or COPD.
 43. The method according toclaim 41, wherein the inflammatory disease is uveitis, and the uveitisis posterior, anterior or pan uveitis.
 44. A process for the preparationof a compound of claim 1, which process comprises the method of any oneof embodiments (a), (b), (c), (d), or (e): (a) reacting a compound offormula II,

wherein LG represents a leaving group, with a compound of formula III,

(b) wherein when L is C(O), reacting a compound of formula IV,

with a compound of formula VIII,

(c) reacting a compound of formula IV,

with a compound of formula IX,

wherein LG¹ is a leaving group; (d) when L is CH₂, alkylating a compoundof formula IV,

with a compound of formula X,

in the presence of a reducing agent; or (e) deprotecting a protectedderivative of a compound of formula I wherein the protected derivativebears a protecting group on an O- or N-atom of the compound of formulaI.